Safety & Efficacy of 68Ga-DOTA-tyr3-Octreotide PET/CT in Diagnosis, Staging & Measurement of Response to Treatment in Patients With Somatostatin Receptor Positive Tumors: Comparison to Octreoscan Plus High-Resolution, Contrast Enhanced CT.
Phase: PHASE1
Conditions: Neuroendocrine Tumors, Carcinoid Tumors, Neuroblastoma, Medulloblastoma
Sponsor: Sue O'Dorisio

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
1 
 
 
 
 
 
 
 
Safety and Efficacy of 68Ga-DOTATOC Positron Emission Tomography 
(PET) for Diagnosis, Staging, and Measurement of Response to 
Treatment in Somatostatin Receptor Positive Tumors 
 
 
 
 
Principal Investigator:  M. Sue O’Dorisio, MD, PhD 
 
Co-Investigators: 
David Bushnell, MD 
Yusuf Menda, MD 
Michael Schultz, PhD, 
Laura Ponto, PhD 
John Sunderland, PhD 
Thomas O’Dorisio, MD 
Michael Graham, PhD, MD 
 
Document type: PROTOCOL FOR IND# 114,398 
Version number: 7 
Date: November 13, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
2 
Summary of Changes 
Version 7 
11/13/2014 
 
Page 
Protocol Changes: 
1 
Changed Version number and date of protocol. 
3 
Revised page numbers. 
10 
Clarified that one nuclear medicine physician will report locations of suspected 
tumor deposits, instead of two physicians. 
11 
Added the number “1” in front of “Adverse Event” for consistency. 
13 
Deleted DSM information as there is no medical monitor for this study.  
Changed risk level of study from 3 to 4.  Added information about DSMC audits 
14 
Removed hyperlink to IRB guidelines for AE reporting. 
14 
Added Expedited AE Reporting table. 
27-31 
Added the Data and Safety Monitoring Plan as Appendix 1 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
3 
 
 
 
 
 
 
 
 
 
 
 
Safety and Efficacy of 
68Ga-DOTATOC Positron Emission Tomography (PET) for Diagnosis, 
Staging, and Measurement of Response to Treatment in Somatostatin 
Receptor Positive Tumors 
 
 
 
TABLE OF CONTENTS 
1. Introduction…………………………………………………………. 4 
2. General Investigational Plan……………………………………… 6 
3. Clinical Protocol……………………………………………………. 7 
4. Chemistry, Manufacturing and Control………………………….. 17 
5. Labeling…………………………………………………………….. 19 
6. Pharmacology and Toxicology…………………………………… 19 
7. Previous Human Experience …………………………………….. 20 
8. References………………………………………………………..... 23 
 
 
Appendices: 
 
I. 
Menda et al., J Nuc Med article on 90Y-DOTATOC therapy in children 
II. 
Bushnell et al., J Clin Oncol article on 90Y-DOTATOC therapy 
III. 
Sample Case Report Form 
IV. 
Materials Specification for 0.1 N HCl 
V. 
Receiving Documentation for 0.1 N HCl 
VI. 
RDRC approved 68Ga-DOTATOC Biodistribution & Reproducibility 
protocol 
VII. IRB approval letter for RDRC protocol using 68Ga-DOTATOC  
VIII. 
Email communications with FDA in regards to Amendment to IND #   
 
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
4 
Project Goal 
Demonstrate the safety and efficacy of [68Ga]-DOTA-tyr3-Octreotide ([68Ga]-DOTATOC) 
as an accurate imaging technique for diagnosis, staging, and monitoring of response to 
treatment in patients with somatostatin receptor expressing tumors. 
 
1.  Introduction: 
Somatostatin Receptor Positive Tumors 
Neuroendocrine tumors are solid malignant tumors that arise from dispersed neuroendocrine cells 
found throughout the body. Gastroenteropancreatic neuroendocrine tumors (NETs) can be divided 
into two groups: Carcinoid tumors that may arise from the lungs, stomach, small bowel or colon and 
pancreatic neuroendocrine tumors (also known as pancreatic islet cell tumors). The clinical behavior 
of NETs is extremely variable; some may cause hormone hypersecretion and others may not, the 
majority of them are slow-growing tumors (well-differentiated NETs), whereas some NETs are highly 
aggressive (poorly differentiated NETs). The incidence of NETs is increasing, from 1.1/100,000 per 
year in 1973 to 5.3/100,000 per year in 20041. Among NETs, 25% have distant metastases and 25% 
have regional involvement at the time of initial diagnosis1.  Other tumors that express high levels of 
somatostatin receptors include neuroblastoma, medulloblastoma, and Ewing’s sarcoma2-4. 
The radiological detection and staging of these tumors is challenging and requires a multimodality 
approach. Somatostatin receptor imaging with In-111 Pentetreotide (OctreoScan) and multiphase 
CT are the most commonly used modalities although the use of endoscopic ultrasound and MRI is 
also increasing. Surgery is the only curative option for NETs. However, curative surgery in malignant 
NET is possible in less than 30% of patients with recurrence identified in the majority of patients as 
late as 15 years after initial surgery. Treatment with somatostatin analogs, which include the short 
acting subcutaneous and long acting release (LAR) octreotide, are effective in stabilizing NETs and 
have been recently demonstrated to prolong the time to progression of disease5. Chemotherapy is 
generally not effective in low grade NETs, but it may be helpful in high grade and pancreatic NETs.  
On the other hand, neuroblastoma, medulloblastoma, and Ewing’s sarcoma are initially responsive 
to chemotherapy, but relapses are common and salvage therapies are not very effective, resulting in 
<30% overall survival at 5 years6-8. 
 
Somatostatin Receptor Targeted Imaging and Therapy  
Tumors that express somatostatin receptors can be targeted with radiolabeled somatostatin 
analogues for imaging and treatment (Figure 1). Somatostatin receptor gamma camera imaging with 
Figure 1: Conceptual representation of 
targeted molecular imaging and therapy of 
cancerous tumors. A cell surface receptor is 
identified that is upregulated in cancerous 
tumor cell relative to normal surrounding tissue 
and organs. A peptide vector is developed that 
binds with high affinity and specificity to the 
molecular target. A chelator is added to the 
targeting vector via a molecular linker. The 
chelator can be used to couple a positron 
emitter as the reporter signal for PET, or with a 
beta emitting radionuclide (e.g., 90Y) for 
molecular therapy. To be effective, the high 
binding affinity of the vector for the target 
antigen and the stable (high specific activity 
radiometallation must be maintained after 
placement of the chemical linker. 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
5 
In-111 DTPA-octreotide (OctreoScan) targeting somatostatin receptor 2 (sstr2), is used routinely for 
imaging of neuroendocrine tumors with a detection rate >90% for well-differentiated carcinoid tumors 
and majority of pancreatic NETs, but only a 50% detection rate for insulinomas, which may show a 
weaker expression of sstr29.   
Given the clinical efficacy of this radiolabeled peptide as a diagnostic agent, studies to test if 
therapeutic radiation could be targeted to tumors in a similar manner was a logical next step. 
Attempts to utilize In-111 DTPA Octreotide as a therapeutic agent have been minimally effective due 
to short range of auger electrons utilized in this therapy. The efficacy of this treatment was improved 
with the development of somatostatin analogues labeled with beta emitting radioisotopes. Further 
studies have identified DOTA as a superior chelator compared to DTPA, increasing the stability and 
receptor targeting of somatostatin analogues10. There is now a large clinical experience with Yttrium-
90 DOTA-tyr3-Octreotide peptide radioreceptor therapy (PRRT) in Europe, primarily in adults with 
neuroendocrine tumors 11. An international Phase II clinical trial then followed and included several 
trial sites in the United States, notably the University of Iowa, where we entered 40 subjects 12. With 
its low toxicity profile, the significant improvement in symptoms and quality of life and the lack of 
effective alternative therapies, PRRT has been suggested as possible first-line therapy in adult 
patients with gastroenteropancreatic neuroendocrine tumor. Recent data have also demonstrated a 
significant survival benefit with PRRT compared to historical controls in this population. We have 
also now conducted a Phase I trial of 90Y-DOTA-tyr3-Octreotide in children and young adults at the 
University of Iowa, which also shows promise of efficacy of this treatment in pediatric patient 
population 13.   We now propose a new imaging agent for use in diagnosis and therapy of 
Somatostatin receptor positive tumors as shown in Figure 2. 
 
 
 
 
 
 
 
 
 
Figure 2  Chemical identity of [68Ga]DOTATOC IND # 114,398 with current IND #61,907 compound 
[90Y]DOTATOC 
Somatostatin Receptor PET Imaging with Ga-68 DOTA0-Tyr3-octreotide  
More recently, positron emission tomography (PET) radiopharmaceuticals have been developed that 
can be labeled with Gallium-68 (Ga-68). Gallium-68 is a generator product with a half-life of 68 min 
(compared to 67 hours for In-111 in OctreoScan). The parent nuclide of Ga-68 is Germanium-68, 
which has a half-life of 270.8 days. Ga-68 decays by 89% through positron emission and 11% by 
electron capture. Its parent, A number of Ga-68 DOTA-conjugated peptides have been introduced, 
including Ga-68 DOTA0-Tyr3]octreotide (Ga-68 DOTATOC), Ga-68 DOTA0-1NaI3-octreotide (Ga-68 
DOTANOC) and [Ga-68 DOTA0-Tyr3]octreotate (Ga-68 DOTATOC). All of these radiolabeled 
peptides bind to sstr2, although DOTANOC also binds to sstr 3 and sstr 5, and DOTATOC to sstr514. 
The primary advantage of Ga-68 based somatostatin receptor PET imaging over OctreoScan 
SPECT is the higher imaging resolution and accurate  quantitation of uptake due to robust 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
6 
attenuation correction. The improved resolution and quantitation of uptake obtained with Ga-68 
DOTATOC PET should provide a more accurate assessment of somatostatin receptor density, 
which will lead to a more accurate prediction of treatment response to somatostatin analogues. A 
recent study from Europe comparing Ga-68 DOTATOC with Octreoscan found Ga-68 DOTATOC to 
be superior in detection of skeletal and pulmonary involvement of neuroendocrine tumors15.  
 2.  Rationale and overall study design 
Rationale: 
68Ga-DOTATOC positron emission tomography (PET) scanning and  90Y-DOTATOC peptide receptor 
radionuclide therapy (PRRT) are readily available in Europe, but neither radiopharmaceutical is 
approved for use in the United States.  IND #61,907 is currently active under the above named 
investigators for 90Y-DOTATOC PRRT in somatostatin receptor positive tumors.  We have conducted 
a single institution Phase I trial of 90Y-DOTATOC  therapy in children and young adults (Appendix I) 
and we have participated in a Phase II trial of 90Y-DOTATOC PRRT in adults (also in Appendix II).  
 
The purpose of this amendment is to test the efficacy of 68Gallium-DOTATOC in diagnosis, staging, 
and determination of response to90Y-DOTATOC PRRT in children and adults with known or 
suspected somatostatin receptor positive tumors, including, but not limited to neuroendocrine 
tumors, neuroblastoma, and medulloblastoma. 68Ga-DOTATOC PET would replace 111In-DTPA-
Octreotide single photon emission tomography (SPECT) imaging.  Whereas, Octreoscan uses a 
222 MBq imaging dose of Indium (2.8 day half life) resulting in an effective dose equivalent (HE) 
equal to 2.61 rads, [68Ga]DOTATOC (68 min half life) uses 185 MBq with an effective dose 
equivalent of 0.46 rads. In addition, [68Ga]DOTATOC PET/CT can be completed within 2 hours 
compared to an Octreoscan which requires 3 visits over 24 hours, making [68Ga]DOTATOC a 
much more convenient imaging choice for patients.  The data obtained in this Ga-68 DOTATOC PET 
study will be used to support the use of 68Ga-DOTATOC PET for diagnosis and staging in patients 
with suspected or proven somatostatin receptor positive tumors. 
 
Overall Study Goal and Study Design 
Project Goal 
This study is planned to demonstrate the safety and efficacy of [68Ga]-DOTA-tyr3-Octreotide ([68Ga]-
DOTATOC) as an accurate imaging technique for diagnosis, staging, and monitoring of response to 
treatment in patients with Somatostatin receptor expressing tumors. 
 
Project Design 
68Ga-DOTATOC Positron Emission Tomography (PET) for Diagnosis, Staging, and Measurement of 
Response to Treatment in Somatostatin Receptor Positive Tumors is a prospective, Phase 1-2, 
single center, open-label study in a total of 112 subjects with known or suspected somatostatin 
receptor positive tumor. Eligible participants will undergo baseline assessments at enrollment. Study 
participants will receive 68Ga-DOTATOC and undergo a PET/CT imaging study with an option to 
receive a second 68Ga-DOTATOC PET/CT if they begin a new treatment (surgery, hepatic 
embolization, Sandostatin LAR, chemotherapy, targeted biological therapy, or peptide receptor 
radiotherapy) within 30 days of the first scan.  The second scan will be performed at a time 
recommended by the treating physician as optimal interval to observe results from treatment. 
 
Participant Enrollment 
Participants will be recruited from the University of Iowa Comprehensive Cancer Center Clinics and 
the University of Iowa Children’s Hospital. Participants who will be approached regarding the study 
are those individuals who are being seen for known or suspected malignancies. 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
7 
 
Schema 
 
Informed Consent 
   
Review pathology report, Octreoscan (if previously performed), CT or MRI, and laboratory tests 
Physical exam with vital signs 
Blood tests (CBC, differential, AST, ALT, bilirubin, BUN, creatinine 
Pregnancy test if indicated 
Injection of 68Ga-DOTATOC 
PET/CT scan 
vital signs 
 
Phone call follow-up 18-36 hrs after PET/CT 
 
Physical exam and blood tests 7-28 days after PET/CT scan 
 
Selected patients will undergo second scan following therapy as recommended by treating physician  
using above schedule. 
 
 2.  Clinical Protocol 
Inclusion Criteria:  
 
• 
Signed informed consent. 
• 
Age ≥ 2 years. 
• 
Known or suspected somatostatin receptor positive tumor such as carcinoid;  
neuroendocrine tumor; neuroblastoma; medulloblastoma; pheochromocytoma.  Supporting 
evidence may include MRI, CT, biochemical markers, and or pathology report.  
• 
Karnofsky performance status or Lansky Play Scale status of ≥ 50 (or ECOG/WHO 
equivalent). 
• 
Subject is male; or is a female who is either pre-menarchal, surgically sterile (has had a 
documented bilateral oophorectomy and/or documented hysterectomy), postmenopausal (> 
1 years without menses), non-lactating, or of childbearing potential for whom a serum 
pregnancy test (with the results known prior to investigational product administration) is 
negative. A negative serum pregnancy test will be required for all female subjects with child 
bearing potential. If a false pregnancy test is suspected, e.g., perimenopausal condition, an 
obstetrician will be consulted to determine if she is/is capable of becoming pregnant. 
 
Exclusion Criteria 
 
• 
Subject weighs more than 400 pounds (Subjects who weigh more than 400 pounds will not 
be able to fit inside the imaging machines). 
• 
Inability to lie still for the entire imaging time (e.g. cough, severe arthritis, etc.) 
• 
Inability to complete the needed investigational and standard-of-care imaging examinations 
due to other reasons (severe claustrophobia, radiation phobia, etc.) 
• 
Does the subject have any additional medical condition, serious intercurrent illness, or other 
extenuating circumstance that, in the opinion of the Investigator, may significantly interfere 
with study compliance? 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
8 
 
Procedures 
 
Informed Consent  
Subjects meeting eligibility criteria will be consented. After consent, subjects are considered actively 
enrolled in the study and a study log will be maintained. Record of consent will be scanned into the 
patient’s electronic chart.  
 
Physical Examination and Medical History  
Physical examination will be performed to ensure suitability according to the inclusion and exclusion 
criteria at screening and baseline and to document the health status and toxicity at the time points 
specified in the Schedule of Events (Table 1).  
 
 
Table 1.  Schedule of Study Events 
 
Visit 
1a 
Scan 
1b 
1 Day 
(18-36 
hours) 
1 wk 
(7-28 
days) 
Scan   
2 
1 day 
1 wk    
(7-28 
days) 
Informed consent  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
X 
 
 
Physical examination 
Xc 
X 
 
 
X 
 
X 
Concomitant meds 
X 
X 
 
X 
X 
 
X 
Blood pressure, temp, 
respiratory rate, heart rate, 
weight 
X 
X 
 
X 
X 
 
X 
CBC, differential, AST, ALT, 
bilirubin, BUN, creatinine 
X 
 
 
X 
X 
 
X 
Pregnancy testd 
X 
X 
 
 
X 
 
 
68Ga-DOTATOC PET/CT 
 
X 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
a To facilitate scheduling, some screening procedures may occur up to 1 month prior to 
the first dose of study drug. 
b Baseline procedures must be performed no more than 7 days prior to study drug. 
c Visit 1 physical exam to include height and performance status. 
d A urine pregnancy test may be done in PET if Visit 1 and Scan 1 are on separate 
days. 
Screening results must be available and baseline procedures performed before the first 
dose of study drug is administered. To avoid repeat tests, some screening values may 
be counted as baseline values if obtained within specified time window. 
 
The physical examination comprises measurement of height and body weight, vital signs of 
temperature, pulse, respiratory rate, and blood pressure. A medical history will be recorded at 
screening and prior to second scan. The medical history will elicit information concerning existing 
medical conditions, major illnesses, and related surgical procedures. Any prescribed or over-the 
counter medications that the subject received within the past 30 days should be recorded on the 
case report form (CRF Appendix III). 
 
Pregnancy Test 
Female subjects of childbearing potential will have a pregnancy test (serum) before exposure to 
research-related radiation.   A woman who is pregnant may not participate in this study and must tell 
us if she may have become pregnant during the previous 14 days because the pregnancy test is 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
9 
unreliable during this time.  If a false pregnancy test is suspected, e.g., perimenopausal condition, 
an obstetrician will be consulted to determine if she is/is capable of becoming pregnant. 
 
 
68Ga-DOTATOC PET/CT Scan 
Study participants will undergo the 68Ga-DOTATOC PET/CT after all screening and baseline 
assessments have been completed. The injected dose will be 3-5 mCi containing <50 ug 68Ga-
DOTATOC and will be injected via IV access lines.   All investigational scans will be read by at least 
two experienced board-certified nuclear medicine physicians with established expertise in PET/CT of 
at least 5 years’ experience.  Readings will be performed independently and blinded to the other 
physician’s interpretation. A data form will be completed prospectively of the site(s) of the primary 
tumor (if visible/present) and metastases. 
 
The scan protocol design will adhere to the As Low As Reasonably Achievable (ALARA) guideline 
for exposure to ionizing radiation (our estimate for the 68Ga-DOTATOC PET scan is 0.46 rad).  Each 
scan will be read independently by two nuclear medicine physicians.  Interpretation discrepancies in 
interpretations will be resolved by consensus of the two interpreting physicians or, in event of failure 
to reconcile, by a third nuclear medicine physician. The final report will then be provided for clinical 
management.  Any controversies will be clearly communicated to the clinical care givers and for data 
analysis.   CT scans of PET-CT will be done for anatomic localization and attenuation correction 
using  a low tube current.  
 
Investigational Radiopharmaceutical Administration 
68Ga-DOTATOC will be administered intravenously in conjunction with the PET/CT scan. The one-
time nominal injected dose will be 3-5 mCi containing <50 μg 68Ga-DOTATOC (estimated, allowing 
for adherence of peptide to glassware or syringes, a portion of the 50 μg original quantity used for 
QC, etc). The normal adult dose will be 4 mCi with adjustments made for smaller body size such that 
the dose will be 0.043 mCi/kg with a minimum dose of 0.3 mCi and a maximum dose of 3 mCi in 
children <18 years old.  
 
 
68Ga-DOTATOC is produced by research chemists who are experienced in clinical and 
investigational radiopharmacy in the University of Iowa PET Center. The University of Iowa PET 
Center staff will conduct the quality control and will approve the final preparation following USP 
<823> standards. Before final release of the agent for administration, release criteria set forth by the 
European pharmacopeia monograph for Gallium (Ga-68) Edotreotide [68Ga]-DOTATOC injection will 
be verified. Bacterial endotoxin testing as well as radiochemical and radionuclidic purity testing will 
also be performed prior to release. In addition to careful observation and monitoring of the patient 
within the PET/CT area for one hour after injection until scan completion (an additional 
approximately 40 – 45 minutes), the patient will be closely monitored in the PET/CT area for a total 
of 2 hours after injection of the radiopharmaceutical. The subject or his/her guardian will be verbally 
asked to identify any symptoms or other change in status that might indicate an adverse reaction to 
the investigational radiopharmaceutical, and will be released only if no adverse events are observed 
(objectively or subjectively). The following day, all subjects will be contacted by phone and again 
asked if untoward/adverse events occurred after release.   One to four weeks following the PET/CT 
scan, subjects will be required to have an AE assessment, vital signs and repeat blood tests. This 
can be done at University of Iowa Hospitals or at a local physician's office.  Information from a local 
visit would need to be faxed to the University of Iowa.  Any observed adverse events will, of course, 
be treated immediately and appropriately, and reported to the University of Iowa IRB and the FDA in 
accordance with established guidelines.  
 
Scan Interpretation: 
Readers of the investigational 68Ga-DOTATOC PET/CT will be blinded to the patient’s identity and to 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
10 
any other clinical information prior to initial interpretation. A board certified nuclear medicine 
physician who is experienced and credentialed in interpretation of clinical PET/CT scan will 
independently report all locations of suspected tumor deposits without discussion with other 
healthcare providers or with correlation with other imaging. In addition to localizing all areas of 
tumor, quantification of size and uptake of up to 5 “target” lesions will be performed (no more than 
two in a given organ), with SUV and cross sectional measurements in long axis and short axis, in 
mm, recorded for each lesion visible on CT.  All of these interpretations (the original and whether or 
not adjudication was needed, and the results of adjudication if performed) will be retained for 
statistical analysis.  Readers will then be asked to review all other available imaging (see next 
paragraph) to see if there are sites of tumor seen on conventional imaging not seen with 68Ga-
DOTATOC on the initial interpretation, and, if so, to determine if this impacted treatment decisions. 
These results will be recorded for statistical analysis. After the investigational 68Ga-DOTATOC 
PET/CT has been independently interpreted, comparison will be made with other, conventional 
imaging (CI), as available. CI used for comparison will include CT scans, MRI scans, 111In-
octreotide scans, ultrasounds and x-ray plain films. Part of data analysis specific to imaging will 
include:  Whether there were sites of tumor seen with 68Ga-DOTATOC PET/CT not seen with CI, 
and, if so, these data will be recorded for statistical analysis  Whether or not the 68Ga-DOTATOC 
PET/CT resulted in a change in stage relative to CI, and, if so, whether it would be up- vs. down- 
staging  Whether or not the 68Ga-DOTATOC PET/CT scan result caused the clinical care givers to 
change treatment, e.g. change within modality (e.g. change chemotherapy, change planned surgery) 
or across modalities (e.g. add chemotherapy or radiation therapy to surgery, etc.). 
 
Risks 
 
Risks of Study Drug 
Research radiation dose estimate: Our calculations estimate that the effective whole-body 
dose of the 68Ga-DOTATOC PET/CT is approximately 1.6 rem, less than the radiation dose 
from a conventional 18F-FDG PET/CT scan of about 2.4 rem, assuming the standard use of a 
“low-dose” CT for anatomic localization and attenuation correction, as described in our 
proposed imaging protocol. The U.S. national annual background dose for humans is 
approximately 0.36 rem.  The maximum annual permissible whole body radiation dose to a career 
radiation worker (e.g., a radiologist, nuclear medicine technologist, etc.) is 5.0 rem. Thus, the one-
time dose to the patient for the investigational PET/CT will be approximately  one-third of the annual 
permissible dose to a career radiation worker and about 5 years’ worth of background radiation in 
the US. Given the average age of the patients in this proposed investigation (about 60 years of age), 
the increased risk to the patient, who will have a known, current life-threatening malignancy, for a 
second, radiation-induced malignancy from this investigational radiation exposure is extremely low 
(estimated < 1%).  Given the risk of death from either delay in diagnosis or under-treatment of these 
known malignancies, we feel the added radiation burden to the patient is well within the patient’s 
best interest if 68Ga-DOTATOC PET/CT imaging adds value.  
 
Risks of Study Procedures  
Risks of Investigational PET/CT: An adverse reaction to the investigational radiopharmaceutical is 
possible though not reported. Additional risks include radiation exposure from the investigational 
PET/CT scan (discussed above), dosage infiltration, risks from IV access. blood tests, and the 
inconvenience of the investigational PET/CT scan. 
 
Children may require sedation or anesthesia to remain still during the PET scanning procedure.  The 
risks of sedation include a reaction to the medication used for sedation or anesthesia.  If anesthesia 
is required, there is a risk of injury to the throat or airways from insertion of the breathing tube. 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
11 
Reporting Adverse Events or Unanticipated Problems involving Risk to Subjects or Others 
 
Adverse Event Terminology 
1. Adverse Event 
An AE is “any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment”. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. AEs include any of the following:  
• 
Subject deterioration due to the primary illness at the onset of the trial 
• 
Intercurrent illnesses 
• 
Drug interactions 
• 
Events related or possibly related to concomitant medications 
• 
Abnormal laboratory values or changes of vital signs, as well as significant shifts from 
baseline within the range of normal, considered to be clinically significant by the Investigator. 
2. Adverse Drug Reaction 
In the pre-approval clinical experience with a new medicinal product or its new usage, particularly as 
the therapeutic dose(s) may not be established, an adverse drug reaction is defined as: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADR). 
3. Unexpected Adverse Drug Reaction 
An unexpected ADR is: 
• 
An adverse drug reaction, the nature or severity of which is not consistent with the applicable 
product information, also known as reference safety information. 
 
4. Serious Adverse Event/Serious Adverse Drug Experience 
During clinical investigations, serious AEs may occur. If the event is suspected to be drug-related, 
the event may be significant enough to lead to important changes in the way the medicinal product is 
developed (e.g. change in dose, population, needed monitoring, consent forms). This is particularly 
true for reactions, which, in their most severe forms, threaten life or function. A serious AE (SAE) or 
serious adverse drug experience (SADE) is any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening. ‘Life-threatening” refers to an event in which the subject is at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe (ICHE6). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/ incapacity (as per reporter’s opinion). 
• 
Is a congenital anomaly/birth defect. 
• 
Is another medically important condition. Important medical conditions that may not result in 
death, be life-threatening or require hospitalization may be considered as SAEs or SADEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed in the definition above. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse 
• 
[Code of Federal Regulations Title 21, Volume 5, 21CFR312.32, revised April 1, 2006]. 
• 
Please note: Serious is not synonymous with severe. An event may be severe (e.g., severe 
headache) but still be of minor medical significance. Serious refers to an event that poses a 
threat to the subject’s life or functioning. 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
12 
5. Assigning Severity to an Adverse Event 
Severity of adverse events will be graded according to NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0) which is available at 
http://ctep.cancer.gov/reporting//ctc.html. 
 
6. Assigning Relationship of Adverse Event to Study Drug (Causality) 
The Investigator will determine the relationship of each ‘probably related’. Descriptions of the three 
classification categories are as follows: 
Not Related 
Exposure to study drug has not occurred; administration of study drug and the adverse event are not 
reasonably related in time; or the AE is considered by the Investigator to be due to a pre-existing 
condition, a known manifestation of the target disease, a recurrent condition, or is likely explained by 
environmental or diagnostic therapeutic factors or was preexisting and did not deteriorate. 
 
Possibly Related 
The AE occurred during or within a reasonable period of time after administration of the study drug, 
or a pre-existing event worsened within an appropriate period of time after administration of study 
drug, but the AE could be explained equally well by factors or causes other than exposure to the 
study drug. This category will also be used if there is a lack of information, or insufficient or 
conflicting evidence exists for classifying the causality of the AE. 
 
Probably Related 
The AE occurred during or within a reasonable period of time after administration of the study drug 
or a pre-existing event worsened within an appropriate period of time after administration of study 
drug, and at least one of the following criteria is applicable: 
• 
the event could not be explained by the clinical condition or history of the subject, 
environmental or toxic factors, or other diagnostic or therapeutic measures; 
• 
the event was an expected ADR associated with study treatment or a class-labeled drug 
effect; 
• 
the AE subsided or disappeared after withdrawal or dose reduction of study treatment; or  
• 
the AE recurred after re-exposure to study treatment. 
 
Adverse Event Recording and Reporting 
Adverse Event Recording 
At baseline, all SAEs and study-related AEs since signing of the Informed Consent Form will be 
recorded. After initial study drug administration, all AEs will be recorded. Each AE occurring to a 
subject, either spontaneously revealed by the subject or observed by the Investigator, whether 
believed by the Investigator to be related or unrelated to the study drug, must be recorded on the AE 
Case Report Form and on the subject’s file. Type and severity of AEs will be reported by the 
subjects without being given a list of fixed symptoms beforehand. The Investigator will also 
determine the relationship of any AE to study drug (causality) and record it on the appropriate 
section of the AE CRF as well as their severity, time of onset, duration, and the precautions carried 
out, and whether or not the event meets one or more of the definitions of an SAE. Laboratory results 
will be recorded on the case report form and the investigator will indicate whether abnormal results 
(high or low) are clinical or not clinically significant. Clinically significant laboratory abnormalities will 
be entered on the ‘Adverse Event Form’ of the CRF. Clinically significant changes in vital signs (e.g., 
tachycardia) or other clinically significant changes observed by the physician will be entered in the 
appropriate CRF. These AEs will also be noted on the ‘Adverse Event Form’ of the CRF as well as 
in the subject file. 
 
Serious Adverse Event Reporting 
All SAEs must be reported promptly to the PI and will follow IRB and IND regulatory reporting 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
13 
requirements. SAEs should be followed to resolution, even if this is after the study reporting period.  
 
 
Data and Safety Monitoring 
 
Assessment of Risk Level: 
This investigation involves risk-level 4 procedures, in a population that is at risk of death> 5% or  
grade 4 – 5 SAE >15%. 
Purpose: 
The Data Safety Monitoring Plan for this study (see Appendix 1) is written to ensure the safety of 
subjects and to verify the validity and integrity of the data. 
DSMC Audits: 
An independent Study Monitor or the DSMC Chair (or designee), will review study data (provided by 
the PI and CRSO) and communicate with the PI at least quarterly.  A copy of this communication will 
be forwarded to the DSMC and PRMC Chairs.  This communication may coincide with the CRSO’s 
quarterly audit when possible.  If an audit has not been conducted—due to lack of research activity--
the quarterly summary letter will occur as scheduled.  
- Subject accrual data will be obtained from OnCore on an ongoing basis by the CTRM during 
accrual review for the PRMC. 
- The research coordinator or data manager for the study will register new subjects in OnCore  
- Adverse events will be reported to the CRSO as defined in the DSMP for the study 
- Serious adverse events will be communicated to the CRSO and recorded in OnCore. 
- The CRSO will contact the research team every three months to coordinate an audit of the 
trial's research records.  Records for a minimum of 25% of subjects will be audited.  OnCore 
auditing functionality will be used to conduct, evaluate, and report on each audit. Audits will: 
o verify eligibility of patients accrued to the study, 
o check for the presence of a signed informed consent, 
o determine compliance with protocol’s study plan, 
o determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies,  
o compare accuracy of data in the research record with the primary source documents, 
o review investigational drug processing and documentation, 
o assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
 
Assessing Toxicity: 
Toxicity will be graded according to NCI’s Common Toxicity Criteria (CTCAE v4). The principal 
investigator will responsible for determining the attribution of toxicity as it is related to the 
investigational drug.  All grades of toxicity will be noted and reported appropriately.  
Adverse Event Reporting:  
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medical treatment or procedure (attribution of unrelated, unlikely, 
possible, probably or definite).” 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
14 
All adverse events associated with the experimental procedures will be reported to the Data Safety 
Monitoring Committee (DSMC) via the Clinical Research Safety Officer (CRSO), as well as the 
appropriate federal regulatory authority, following established guidelines.  Reports to DSMC will be 
sent to the CRSO, entered into OnCore and communicated to the DSMC in a timely manner.  Only 
Grade 4 and 5 events that are unexpected, with at least possible attribution to 68Ga-DOTATOC 
PET, will require an expedited report.  The investigator will continue to follow or obtain 
documentation until the resolution of such an event.   
Adverse events may also require reporting to the IRB per HSO-established guidelines. 
The clinical research coordinator is responsible for collecting and recording all clinical data. As these 
results are collected, all toxicities and adverse events will be identified and reported to the principal 
investigator.  The principal investigator will determine relationship of the event to the study drug and 
decide course of action for the study participant. As part of the ongoing monitoring of this study, the 
PI will maintain an AE summary table to be reviewed during the quarterly audits.   
 
Guidelines for Routine Adverse Event Reporting 
Attribution 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Unlikely 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Possible 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Probable 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Definite 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
 
Expedited Adverse Event Reporting 
Only Grade 4 and 5 events that are unexpected with at least “possible” attribution to the 68Ga-
DOTATOC PET will require an expedited report to the CRSO/DSMC (24-hour notification followed by 
complete report within 5 calendar days).  All expedited adverse event reports will be reviewed by the 
DSMC.   
 
1. EXPEDITED ADVERSE EVENT REPORTING 
 
Table II: Reporting Requirements for Adverse Events that occur within 30 Days1 of the Last Dose of the 
Investigational Agent on Phase 1 Trials 
 
1 
2 
2 
3 
3 
4 & 52 
Unexpect
ed and 
Expected 
Unexpecte
d 
Expecte
d 
Unexpected 
Expected 
Unexpected 
and Expected 
With 
Hospital 
without 
Hospital 
with Hospital 
without 
Hospital 
Unrelate
d 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Require
d 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar 
Days 
24-Hour; 5 
Calendar 
Days 
10 Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar Days 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
15 
1Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 Grade 4 unexpected events 
 Grade 5 expected and unexpected events 
2Although an AdEERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
 
Study Withdrawal/Discontinuation 
This is a low risk imaging protocol; the amount of radioactive peptide is below physiological effects 
level and the radiation dose is below allowable levels.  No adverse events are expected.  Adverse 
events are recorded on the CRF at the following times: 
 
immediately following the PET/CT 
 
at the conclusion of a 2 hrs observation time from time of injection of radiopharmaceutical 
 
during phone call 18-24 hrs after PET/CT 
 
one to four weeks following PET/CT at outpatient visit with physical exam and labs 
 
Subjects will be entered in groups of three; if one of the first 3 subjects experiences a grade 3 or 4 
adverse event, another 3 will be entered.  If two of six subjects experience grade 3 or 4 adverse 
event, the study will be stopped.  Otherwise an additional 14 subjects will be entered.  If three of 20 
subjects experience grade 3 or 4 adverse event, the study will be stopped.  if < 3/20 subjects 
experience grade 3 or 4 adverse event, the radiopharmaceutical will be considered safe. 
 
At any time, subjects may withdraw from the study (i.e., withdraw consent to participate) at their own 
request. A subject’s participation in the study may be discontinued at any time at the discretion of 
the Investigator and in accordance with his/her clinical judgment. No disadvantage will arise for any 
subject who withdraws consent for participation at any time or who is withdrawn from the study by 
the Investigator.  Reasons for discontinuation of study treatment will be recorded on the appropriate 
page of the CRF in any case and may include the following: 
• 
Subject's request for withdrawal 
• 
Investigator's decision that discontinuation is in the best interest of the subject 
• 
Non-compliance with the regimen and timing that might result in dropping out from the study 
• 
Development of an intolerable AE due to study participation as determined by the 
Investigator, subject, or both. 
• 
Development of an intercurrent illness, condition, or procedural complication, which would 
interfere with the subject's continued participation. 
• 
Subject is lost to follow-up. 
 
Subjects who discontinue treatment will be asked to complete a follow-up examination prior to 
leaving the study, if possible.   Any subject who discontinues treatment for medical reasons, e.g. 
because of adverse events (AEs) or clinical laboratory abnormalities, should be followed up at 
medically appropriate intervals in order to evaluate the course and to ensure reversibility or 
stabilization of the abnormality or event. If a subject fails to return for a scheduled visit, a 
documented effort must be made to determine the reason. This information should be recorded in 
the study records. 
 
Statistical Considerations 
The distribution of patients will be an important element of statistical consideration. Several types of 
patients will be studied, including patients with: 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
16 
• 
Primary pancreatic, small bowel, or lung neuroendocrine tumor 
• 
Metastatic pancreatic, small bowel or lung neuroendocrine tumor 
• 
Primary or metastatic neuroblastoma 
• 
Primary or metastatic medulloblastoma 
• 
Primary or metastatic pheochromocytoma 
Given the distribution of patients seen at the University of Iowa Hospitals, an excellent distribution of 
patients will be enrolled. We predict that with a total of 153 subjects, each of the above types of 
diagnoses will be captured and accuracy of the 68Ga-DOTATOC PET/CT can be adequately studied. 
We will observe for adverse events related to the use of the 68Ga-DOTATOC radiopharmaceutical in 
accordance with NCI toxicity guidelines (described below) in order to provide the FDA and ourselves 
with important, traceable toxicity/safety data regarding the use of this investigational 
radiopharmaceutical.  In those patients with available conventional imaging (Octreoscan, high-
resolution, contrast CT or MRI), we will determine if the 68Ga-DOTATOC PET/CT scan alters care of 
patients  and whether or not conventional imaging demonstrated negative or equivocal evidence of 
tumor size and location in the same patients.  Many of our patients will be referred from outside 
centers with conventional imaging (CT, MRI and 111In-Octreotide scans) already accomplished. We 
will assess for an impact on treatment by determining if a given patient’s care is altered after the 
results of the 68Ga-DOTATOC PET/CT scan are available. 
 
For those patients who have available CT, MRI or Octreoscan, we will determine equivalence of 
conventional imaging and 68Ga-DOTATOC PET using percentage of concordance in tumor 
detection. We hypothesize that less than 80% agreement on their assessment would be inconclusive 
while more than 90% agreement on their assessment would favor equivalence.  We define an 
indicator variable for [68Ga]DOTATOC PET/CT findings (+/-) and another indicator variable for 
Octreoscan findings (+/-). Positive findings are labeled (+) while negative findings are (-); with 
concordance [68Ga]DOTATOC PET/CT vs. Octreoscan occurring at the combinations (+/+) and     
(-/-), and discordance occurring at (+/-) or (-/+).  
Since the same patient is measured under both tumor detection methods (conventional 
imaging and 68Ga-DOTATOC PET/CT), we base our sample size and power justification on the 
proportion of concordance and on the proportion of discordance.  This outcome is of direct benefit to 
patient population. This analysis requires 112 patients to decide whether the proportion of 
agreement between the two assessment methods is less than or equal to 80% or greater than or 
equal to 90%. If 97 or more subjects result in the same decision on both [68Ga]DOTATOC PET/CT 
and conventional imaging, the null hypothesis that P <= 80% would be rejected in favor of the 
alternative. The expected error rate is alpha = 0.05 and the actual error rate of 0.047. If this number 
of subjects with concordant decision is 96 or less, the hypothesis that P >= 90% is rejected with a 
target error rate of 10% and an actual error rate of 0.092. The power of the test is 90%. 
In case the null of P <= 80% is accepted, we have at least 20% chance of assessing 
discordance. This percentage (~22 subjects) is then used to search for false positives and false 
negatives. Pilot data suggests more subjects may fall within the category +/- (i.e. positive 
[68Ga]DOTATOC PET/CT, negative Octreoscan).   
Note: There is a source of bias in this design. Subjects receive treatment based on positive 
findings from Octreoscan + diagnostic CT, the composite gold standard, regardless of their 
discordance with [68Ga]DOTATOC PET/CT.  Bias came about because the cohort -/+ (i.e. 
[68Ga]DOTATOC PET/CT (-) and composite gold standard (+)) would receive treatment regardless of 
[68Ga]DOTATOC PET/CT finding. This bias should not create a commotion because the scenario -/+ 
would be rare based on pilot finding. The discordance +/- (i.e. [68Ga]DOTATOC PET/CT (+) and 
composite gold standard (-)) is more important at showing the advantage of [68Ga]DOTATOC 
PET/CT. This discordance would yield a population greater than 22 if concordance is less than 80% 
and a population <22 otherwise. 
Binomial exact tests would be used on this discordant population after biopsy and after 6-
month follow up to detect whether the proportion discovered after biopsy (or follow up) is significantly 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
17 
smaller or comparable to the population claimed by [68Ga]DOTATOC PET/CT findings. This will also 
serve as false positive rate assessment if not confirmed at follow up.  On a more general note for 
discordance/concordance study design, a sample of size 112 (or a set of 112 pairs of assessment) 
will achieve 99% power to detect an odds ratio of 12.33 using a two-sided McNemar test with a 
significance level 0.05. The odds ratio is equivalent to a difference between 2 paired proportions of 
17% which occurs when the proportion of   -/+ is 1.5% (i.e. [68Ga]DOTATOC PET/CT negative; 
composite gold standard positive) and the proportion in +/- is 18.5% (i.e. [68Ga]DOTATOC PET/CT 
positive; composite gold standard negative ), and the total discordance is 20%. 
 
Power Table  
Sample 
Size 
Power 
Odds 
Ratio 
-/+ 
Rate 
+/-Rate 
Alpha 
 
112 
99% 
12.33 
1.5% 
18.5% 
0.05 
112 
96% 
7.00 
2.5% 
17.5% 
0.05 
112 
86% 
4.71 
3.5% 
16.5% 
0.05 
112 
79% 
4.00 
4.0% 
16.0% 
0.05 
 
 
 
Privacy/Confidentiality Issues 
All routine medical data will be entered into the patient’s electronic medical record.  These records 
are only available to those with direct clinical duties to the patient. For all other records, the Principal 
investigator will collect data and enter it into password protected computer in a locked office. Each 
patient will have a unique identifier number, with the key to the patient’s medical record number kept 
in a locked cabinet in the office.  Only research associates or those individuals directly involved with 
the study will have access to data. Information is for research purposes only and when used for 
publication purposes, all participants will have their names concealed. Access to identified patient 
information will be limited to the investigators listed within the IRB application. De-identified 
information with HIPAA identifiers removed will be available to other investigators following IRB 
approval. Confidentiality and security will be maintained for the database. 
 
The database is stored behind a firewall (in addition to the institutional firewall) with the highest level 
of protection, i.e. the same level of protection as the on-line hospital information systems at the 
University of Iowa Hospitals . This means that users must logon to a web server that sits between 
the institutional firewall and the firewall to the database, and only this application server is allowed to 
query the database. Only users approved through our institutional review boards will be allowed 
access to patient identifiers. Other levels of authorization may exist for future approved users 
following IRB approval, e.g. access to de-identified data. 
 
Data is initially collected in the medical record for each individual study participant. The information 
will be extracted from the patient’s medical record and then transferred into the Case Report Form 
(CRF). The study data will be kept on site and in a securely locked room to protect patient 
confidentiality. The CRFs do not include personal identifiers for any participant. Numbers and initials 
are assigned for each participant and these become the identifying information for each study 
participant. A master list is kept separately that identifies which names go with which numbers and 
initials. Study personnel (PI and co-investigators) and government regulatory agencies have access 
to all research records as required by law. Others (such as law enforcement agencies) may have 
access to records as defined by law. 
 
Record Retention 
The PI must retain all study records by the applicable regulations in a secure and safe facility. The 
institution must consult with the PI before disposal of any study records, and must notify the PI of 
any change in the location, disposition or custody of the study files. The PI/institution must take 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
18 
measures to prevent accidental or premature destruction of essential documents, that is, documents 
that individually and collectively permit evaluation of the conduct of a study and the quality of the 
data produced, including paper copies of study records (e.g., subject charts) as well as any original 
source documents that are electronic as required by applicable regulatory requirements. Records 
and documents pertaining to the conduct of this study, including Case Report Forms (Appendix III), 
source documents, consent forms, laboratory test results, and medication inventory records, must 
be retained by the investigator for at least 2 years following submission of a New Drug Application. 
No study records will be destroyed without prior authorization from the Principal Investigator. 
 
4. Chemistry, Manufacturing, and Control 
The University of Iowa PET Center Radiopharmaceutical Laboratory maintains an environment that 
is adherent to USP <823>. Reagents used for the preparation of [68Ga]-DOTATOC are received and 
inspected per specification sheets (e.g., see 0.1 N HCl Specification Sheet, Appendix IV) and 
accepted or rejected.  Accepted reagents are labeled with appropriate expiration dates, initialed, 
assigned identification numbers (e.g., see Receiving Document 0.1 N HCl Appendix V), and 
quarantined in specified locations in the radiopharmaceutical laboratory.  
 
The University of Iowa (UI) PET Center Radiopharmaceutical Laboratory is staffed with expert 
radiochemists that oversee the preparation of the radiopharmaceuticals and are experienced in the 
compounding of the proposed investigational radiopharmaceutical because of its ongoing use under 
Radioactive Drug Research Committee approval (Biodistribution and Reproducibility of Ga-68 
DOTATOC Positron Emission Tomography in Patients with Somatostatin Receptor Positive Tumors:  
A Feasibility Study; University of Iowa IRB # 201012803).  
 
Because Ga-68 has a 68 minute half life, production of [Ga-68]DOTATOC requires the use of a 
Germanium-68 (Ge-68) to Ga-68 generator. The eluted Ga-68 is purified following elution using an 
ion-exchange column prior to introduction into the radiolabeling vessel with DOTATOC to remove 
zinc-68 (the decay product of Ga-68), which builds up in the generator with the decay of Ga-68. 
 
According to the [Ga-68]DOTATOC Batch Record, the generator is connected to the ModularLab 
PharmTracer module and eluted with 0.1 N HCl directly to an ion exchange column for purification of 
the Ga-68 from Zn-68 (daughter nuclide of Ga-68 decay). The system includes a disposable GMP-
certified (sterile, pyrogen-free) “kit” that is snapped in place and manages (via software) the flow of 
reagents for purification, radiolabeling, and transfer of the final product to the product vial via 
sterilizing (0.22 μm filter). A new kit is used for each preparation and preparations are usually used 
for a single patient study. At the end of the process, the generator line is disconnected, capped, and 
the generator stands ready for connection to a new kit for a new preparation. 
 
The system then elutes Ga-68 with acetone/0.02 N HCl solution directly to a reaction vessel 
containing 40 micrograms of DOTATOC (obtained commercially) dissolved in 2 mL of sodium 
acetate buffer (pH 4). The solution is heated to 95 °C for 7 minutes at which time the heating 
element is turned off and the vessel is cooled with the addition of 2 mL isotonic saline for injection. 
Acetone is removed by distillation during the radiolabeling process and a test for residual is included 
in subsequent quality control prior to release.  
 
The solution is next passed over a disposable C-18 cartridge, which retains [Ga-68]DOTATOC, while 
allowing any remaining free Ga-68 to pass. The cartridge is rinsed with isotonic saline for injection to 
remove any residual free Ga-68, followed by elution of [Ga-68]DOTATOC with 1 mL 47.5% ethanol 
in isotonic saline for injection directly through a sterile 0.22 micron membrane filter into the final 
collection vial.  
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
19 
A 0.8 mL aliquot is then taken for quality control testing and the product line and vent filter are 
removed. Radiochemical yields of approximately 55% (uncorrected for decay) are routinely achieved 
using this process. The filter is retained for a QC pressure test to ensure filter integrity for 
sterilization. The production process can be conducted by a single person and requires 
approximately 1 hr to complete. Quality control procedures are usually carried out by two persons to 
expedite delivery of the final product vial for human use when QC parameter testing has been 
completed. The QC process takes approximately 20 minutes. 
 
The quality control tests are performed and compared to release criteria prior to release of the final 
product as shown in Table 2. 
 
Table 2. Analytical Specifications 
 
Test 
Release Criteria 
 
 
Appearance 
Clear and no visible impurities 
Filter Test 
2 bar for 1 minute 
pH 
3.0 – 7.0 
Radiochemical 
>90% 
Endotoxins 
<17.5 EU per mL 
Acetone 
<5000 ppm 
Ethanol 
<10% 
Radionuclidic 
Half life +/- 90 seconds 
 
 
Filter Test: A filter pressure test is conducted by applying pressure to the sterilizing filter at 2 bar 
inert gas (nitrogen or argon) for 1 minute to ensure the integrity of the filter for sterilization. 
 
Bacterial Endotoxins: Bacterial endotoxin test following a 50:1 dilution. Endotoxin/Limulus 
Amebocyte Lysate (LAL) testing using Endosafe-PTS Cartridges or alternative gel-clot vials as 
backup. 
 
pH: The pH of the final product should fall within the limits of 4.0-7.0 and is measured by spotting pH 
paper. 
 
Radiochemical Purity: The system utilizes ITLC-SG media and 0.2 M Citric acid: ethanol (90:10) 
as the solvent. When using this TLC system, colloidal Ga-68, Ga68-DOTATOC, and free Ga-68 can 
be differentiated at rf – 0.0, 0.5 and 1.0, respectively.  
 
Sterility: Following release, Tryptic Soy Broth (TSB) and Fluid Thioglycollate Media (FTM) are 
inoculated, incubated (TSB at room temp, FTM at 36 C) and checked for growth during the following 
14 days. At the completion of the sterility test, the batch record is completed and filed. 
 
Acetone: When acetone is used in the purification process, a gas chromatography test is used for 
analytical specification. 
 
Ethanol: When ethanol is used in the purification process, a gas chromatography test is used for 
analytical specification. 
 
Radionuclidic Purity: Half life measurement is determined by continuous measurement of 
radioactivity signal over 5 minutes and evaluation of the slope of the decay curve.  The half life 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
20 
specification is obtained from Evaluated Nuclear Structure Data File (ENSDF) at the National 
Nuclear Data Center (NNDC) which can be accessed at www.nndc.gov . Additional standard 
operating procedures include out of specification investigations and reprocessing in the event of a 
0.22 micron filter failure. 
 
CMC REFERENCES: 
1. Ocak et al., Full automation of 68Ga labelling of DOTA-peptides including a cation exchange pre-
purification. (2010). Appl. Rad. Isot., 68;297-302. 
2. Velikyan I., Positron Emitting 68Ga-Based Imaging Agents: Chemistry and Diversity. Med. Chem. 
2011 Jun 28. [Epub ahead of print]. 
3. Capello et al., Cancer Biother. Radiopharm., 18, 761 (2003) 
4. Breeman et al., Eur. J. Nucl. Med. Mol. Imaging, 30, 917 (2003) 
5. de Jong et al., J. Nucl. Med., 46, 13S (2005) 
6. Valkema et al., J. Nucl. Med., 46, 83S (2005) 
7. L.Kolby et al., Br. J. Cancer, 93, 1144 (2005) 
8. Gallium-68 Half Life. Evaluated Nuclear Structure Data File (ENSDF); www.nndc.gov. 
 
5. Labeling 
Each unit dose will be made at the time of use, within one hour, due to the 68 minute half-life of the 
68Ga radiopharmaceutical, and labeled with the patient’s name and ID in accordance with the usual 
and customary practice of radiopharmacy at the University of Iowa PET Center. The standard label 
includes patient name, medical identification number, time/date of completion of compounding, and 
identity of the radiopharmaceutical; all necessary information will be available.  
 
The amount of radioactivity injected into the patient’s IV will be recorded immediately prior to 
injection, with residual activity in the syringe recorded immediately after injection. The dose 
calibrators used in the University of Iowa are regularly maintained and calibrated in accordance with 
current NRC standards.  An investigational record will be maintained with a copy of each drug label, 
also documenting time of injection, pre- and post-injection activity, time and date of injection, and 
patient identification information. Investigational radiopharmaceutical QA/QC information will be 
maintained for each unit dose for at least six years after the closure of this study. These data will 
provide important information should there be need to perform a rootcause analysis for a failure-to-
perform of a given investigational PET/CT scan. 
 
6. Pharmacology and Toxicology Information 
The below summary of human experience provides strong evidence that the amount of 
investigational drug (DOTATOC) in mass quantity and the amount of radiation (as also provided via 
our measured radiation dosimetry) are acceptable in terms of risk. The NOAEL level of DOTATOC 
has never been established in humans, despite some of the below studies reporting much larger 
mass quantity use than we propose, with some using multiple large doses5.  The radiation toxicity 
from the investigational radioisotope is also, accordingly, within the acceptable range for patients 
with life-threatening malignancies whose treatment we believe will benefit from the use of the 
proposed investigational imaging procedure.  Accordingly, we believe the risk/benefit of our 
proposed investigation to be justified. 
 
7.  Previous Human Experience 
 
Experience at the University of Iowa 
Although there is extensive use of [68Ga]DOTATOC PET/CT in Europe, the limited US experience is 
outlined here. The University of Iowa Radioactive Drug Research Committee and Institutional 
Review Board approved a study entitled “Biodistribution and Reproducibility of Ga-68 DOTATOC 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
21 
Positron Emission Tomography in Patients with Somatostatin Receptor Positive Tumors:  A 
Feasibility Study” in March, 2011 (Appendices VI and VII.  Subjects received two [68Ga]-DOTATOC 
PET/CT scans within 36 hours on each of five subjects who were selected based on biopsy proven 
NET with a positive Octreoscan™ within the past 3 months. [68Ga]DOTATOC was prepared with 
GMP grade DOTATOC from Molecular Insight Pharmaceuticals using the Eckert-Zeigler ModularLab 
PharmTracer system. A comparison study is shown in Figure 3; the number of lesions is clearly 
greater with [68Ga]DOTATOC PET compared to Octreoscan; biodistribution and reproducibility for 
these five subjects is summarized in Fig 4 &Table 3. 
 
 
 
Figure 3.  [68Ga]-DOTATOC PET/CT in patient with biomarkers and liver mets suggestive of ileal NET, but 
primary not seen on either high-resolution, contrast CT or Octreoscan.  Arrows indicate ileal lesion clearly 
demonstrated on PET/CT with [68Ga]-DOTATOC that was (in retrospect) faintly visible on Octreoscan.  
Unknown primary lesion in ileum confirmed by surgical exploration.  Also note addition liver lesions seen on 
[68Ga]-DOTATOC PET/CT. 
 
 
 
 
Table 3. SUVmax reproducibility of [68Ga]-DOTATOC PET lesions 
 in patients with metastatic NETs 
 
  
Subject 1 
 
Subject 2 
Subject 3 
Subject 4 
Subject 5 
Total 
Organs Involved 
Pancreas, bone, 
LN, peritoneum 
Lung, bone, 
LN, liver 
Heart, liver, LN 
Bone, liver, 
LN 
Lung, bone, LN, 
liver, sm bowel 
 
 
% Error * 
5 target lesions 
7.6 ± 7.3 
11.8 ± 9.9 
11.8 ± 7.8 
4.6 ± 4.0 
9.2 ± 5.9 
9.0 ± 7.1 
% Error * 
10 target lesions 
10.4 ± 10.4 
15.7 ± 16.3 
7.4 ± 7.4 
5.0 ± 3.9 
10.7 ± 6.2 
9.8 ± 10.1 
To evaluate the reproducibility of measurement of uptake of 68Ga DOTATOC, 5 patients with metastatic NET 
underwent two DOTATOC PET scans. Standardized uptake values (SUVmax) were measured for 5 target 
lesions (max 2 per organ) and 10 target lesions (max 5 per organ) per subject. Target lesions included 
representative lesions from all involved organs and the lesions with the highest activity for each involved 
organ. Percentage error (i.e. reproducibility) was calculated for each lesion as Percentage Error = 100*ABS 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
22 
(Scan 2-Scan 1)/((Scan 2 + Scan 1)/2))16.                     
 
*mean + standard deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Production of [68 Ga]DOTATOC at University of Iowa 
The cGMP grade DOTATOC was purchased from Bachem with the written permission of Molecular 
Insight Pharmaceuticals, Inc.  Radiolabeling was performed using a TiO2 germanium-gallium 
generator and automated ModularLab PharmTracer, both from Eckert-Zeigler Eurotope GmbH.  This 
system utilizes a sterile cassette that is replaced for each radiolabeling procedure.  Performance has 
been very reproducible with radiochemical, radionuclic, sterility as shown in Table 4. 
 
 
Figure 4.  Reproducibility of [68Ga]DOTATOC PET in patients with NET.  Results for each subject and all 
target lesions in Table 2 are shown. The average (mean ± SD) reproducibility was 10% ±10% for 50 target 
lesions. The scatter graph (excluding 2 lesions with SUV>50 for display purposes) shows the high 
correlation of SUVmax of all target lesions on Scan 1 and 2 (R2=0.99).  

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
23 
 
European Experience in Humans 
The potential of [68Ga]DOTATOC PET/CT for improved imaging of somatostatin receptor positive 
tumors has been recognized since early comparative studies noted improvements in detection 
sensitivity and image quality in comparison to [111In]DTPA-octreotide SPECT17. Although we have 
successfully employed [111In]DTPA-octreotide SPECT/CT (Octreoscan) + a diagnostic CT for 
diagnosis, staging, and monitoring of NET in children and adults2,18, our RDRC approved studies 
(Figures 3 and 4) as well as comparisons of [68Ga]DOTATOC and Octreoscan by European 
investigators, support our hypothesis that [68Ga]DOTATOC will provide at least equivalent, and likely 
objective improvements in, diagnosis and staging of neuroendocrine tumors and other somatostatin 
receptor positive tumors19-21. Several advantages of [68Ga]DOTATOC PET/CT have been pointed out 
through these published studies. For example, Gabriel and colleagues concluded that 
[68Ga]DOTATOC PET/CT shows a significantly higher detection rate (higher sensitivity) compared to 
conventional Octreoscan SPECT/CT based on a randomized prospective study. These findings are 
corroborated by a prospective study concluding that [68Ga]DOTATOC PET was superior to 
Octreoscan in detection of metastases in the lung, skeleton, liver, and brain15.  A study 
demonstrating that [68Ga]DOTATOC PET influences patient management in ≥ 33% of patients further 
supports the introduction of this imaging technique into the United States22.  
 
Comparisons of [68Ga]DOTATOC and Octreoscan by European investigators, support our early 
observations that [68Ga]DOTATOC will provide at least equivalent, and likely objective improvements 
in, diagnosis and staging of NETs19-21. Several advantages of [68Ga]DOTATOC PET/CT have been 
pointed out through these published studies. For example, Gabriel and colleagues concluded that 
[68Ga]DOTATOC PET/CT shows a significantly higher detection rate (higher sensitivity) compared to 
conventional Octreoscan SPECT/CT based on a randomized prospective study. These findings are 
corroborated by a prospective study concluding that [68Ga]DOTATOC PET was superior to 
Octreoscan in detection of NET metastases in the lung, skeleton, liver, and brain15.  A study 
demonstrating that [68Ga]DOTATOC PET influences patient management in ≥ 33% of patients further 
supports our proposed research22. 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
24 
Request for Permission to Charge for an Investigational Drug under an IND 
 
This application is seeking FDA approval to charge for the cost of producing 68Ga-DOTATOC to be 
used as a PET tracer.  Costs are justified under Title 21, Chapter 1, Subchapter D Drugs for Human 
Use, Part 312, IND application as outlined below: 
 
 
312.8b (i). 68Ga-DOTATOC PET will be used in this clinical trial as a replacement for 
Octreoscan SPECT imaging.   As stated in our IND application, the primary advantage of Ga-68 
based somatostatin receptor PET imaging over OctreoScan SPECT is the higher imaging resolution 
and accurate  quantitation of uptake due to robust attenuation correction. The improved resolution 
and quantitation of uptake obtained with Ga-68 DOTATOC PET should provide a more accurate 
assessment of somatostatin receptor density, which will lead to a more accurate prediction of 
treatment response to somatostatin analogues. A recent study from Europe comparing Ga-68 
DOTATOC with Octreoscan found Ga-68 DOTATOC to be superior in detection of skeletal and 
pulmonary involvement of neuroendocrine tumors15.  Additional advantages for patients include the 
lower radiation dose and the shorter imaging time. Whereas, Octreoscan uses a 222 MBq imaging 
dose of Indium (2.8 day half life) resulting in an effective dose equivalent (HE) equal to 2.61 rads, 
[68Ga]DOTATOC (68 min half life) uses 185 MBq with an effective dose equivalent of 0.46 rads. In 
addition, [68Ga]DOTATOC PET/CT can be completed within 2 hours compared to an Octreoscan 
which requires 3 visits over 24 hours, making [68Ga]DOTATOC a much more convenient imaging 
choice for patients. 
 
 
312.8b (ii).  The imaging trial proposed under this IND will enroll up to 153 subjects, ages 2 – 
100 years of age with Somatostatin receptor positive tumors, many of whom will have had a recent 
Octreoscan and/or high-resolution, contrast-enhanced CT or MRI.  The tumor types include 
neuroendocrine tumors, neuroblastoma, medulloblastoma, and pheochromocytoma.  The study will 
thus test both efficacy and safety in adults and children with multiple tumor types. 
 
 
312.8b(iii). [68Ga]DOTATOC will be produced at the University of Iowa PET Center.  The 
extraordinary cost of producing [68Ga]DOTATOC precludes performance of the study without 
charging due to manufacturing complexity.  The direct costs include purchase and storage of the 
synthetic peptide, DOTATOC; a gallium generator every 6 months to produce the short lived isotope; 
chemicals required in the radiolabeling procedure; a specialized ModularLab to ensure 
reproducibility of the product and safety of the radiochemists; single use radiolabeling cassettes to 
ensure sterility of the product; personnel costs for the radiochemists; and the base cost of the 
PET/CT imaging. 
 
 
312.8c.  Because [68Ga]DOTATOC has a 68 minute half-life, it will need to be produced 
locally when trials are expanded to other centers.  We intend to provide the protocol as well as all 
required Standards of Procedure associated with this IND to the Society of Nuclear Medicine Clinical 
Trials Network.  We will apply for expanded access charging at that time, if appropriate. 
 
Charges will be paid by the subject or the subject’s insurance company with the exception that the 
scans for children < 17 yrs with brain tumors may be paid from a childhood brain tumor research 
account in the University of Iowa Foundation.  
 
  
References:  
 
1. 
Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and 
prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of 
Clinical Oncology. 2008;26(18):3063-3072. 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
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2. 
O'Dorisio MS, Khanna G, Bushnell D. Combining anatomic and molecularly targeted imaging 
in the diagnosis and surveillance of embryonal tumors of the nervous and endocrine systems in 
children. Cancer Metastasis Review. 2008;27(4):665-677. 
3. 
Fruhwald MC, O'Dorisio MS, Pietsch T, Reubi JC. High expression of somatostatin receptor 
subtype 2 (sst2) in medulloblastoma: implications for diagnosis and therapy. Pediatric Research. 
1999;45(5 Pt 1):697-708. 
4. 
Juweid ME, Menda Y, O'Dorisio MS, et al. 111In-pentetreotide versus bone scintigraphy in 
the detection of bony metastases of neuroblastoma. NuclMed Commun. 2002;23(10):983-989. 
5. 
Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, 
randomized study on the effect of octreotide LAR in the control of tumor growth in patients with 
metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 
2009;27(28):4656-4663.  
6. 
DuBois SG, Messina J, Maris JM, et al. Hematologic toxicity of high-dose iodine-131-
metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22(12):2452-
2460. 
7. 
Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system 
embryonal tumour outcome based on gene expression. Nature. 2002;415(6870):436-442. 
8. 
Thacker MM, Temple HT, Scully SP. Current treatment for Ewing's sarcoma. 
ExpertRevAnticancer Ther. 2005;5(2):319-331. 
9. 
Kwekkeboom DJ, de Herder WW, van Eijck CH, et al. Peptide receptor radionuclide therapy 
in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med;40(2):78-88.  
10. 
Kwekkeboom DJ, Bakker WH, Kooij PP, et al. [177Lu-DOTAOTyr3]octreotate: comparison 
with [111In-DTPAo]octreotide in patients. EurJNuclMed. 2001;28(9):1319-1325. 
11. 
Forrer F, Waldherr C, Maecke HR, Mueller-Brand J. Targeted radionuclide therapy with 90Y-
DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006;26(1B):703-707. 
12. 
Bushnell DL, Jr., O'Dorisio TM, O'Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid 
refractory to octreotide. J Clin Oncol. 2010;28(10):1652-1659.  
13. 
Menda Y, O'Dorisio MS, Kao S, et al. Phase I trial of 90Y-DOTATOC therapy in children and 
young adults with refractory solid tumors that express somatostatin receptors. J Nucl Med. 
2010;51(10):1524-1531.  
14. 
Wild D, Macke HR, Waser B, et al. 68Ga-DOTANOC: a first compound for PET imaging with 
high affinity for somatostatin receptor subtypes 2 and 5. EurJNuclMedMolImaging. 2005;32(6):724. 
15. 
Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-
DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. EurJNuclMedMolImaging. 
2007;34(10):1617-1626. 
16. 
Shields AF, Lawhorn-Crews JM, Briston DA, et al. Analysis and reproducibility of 3'-Deoxy-3'-
[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung 
cancer. Clin Cancer Res. 2008;14(14):4463-4468.  
17. 
Hofmann M, Maecke H, Borner R, et al. Biokinetics and imaging with the somatostatin 
receptor PET radioligand (68)Ga-DOTATOC: preliminary data. EurJNuclMed. 2001;28(12):1751-
1757. 
18. 
Khanna G, O'Dorisio MS, Menda Y, Kirby P, Kao S, Sato Y. Gastroenteropancreatic 
Neuroendocrine Tumors in Children and Young Adults. Pediatric Radiology. 2008;38:251-259. 
19. 
Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in 
neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. JNuclMed. 
2007;48(4):508-518. 
20. 
Jindal T, Kumar A, Venkitaraman B, Dutta R, Kumar R. Role of (68)Ga-DOTATOC PET/CT in 
the evaluation of primary pulmonary carcinoids. Korean J Intern Med. 2010;25(4):386-391. 
Prepublished on 2010/12/24 as DOI 10.3904/kjim.2010.25.4.386. 
21. 
Jindal T, Kumar A, Kumar R, Dutta R. Role of 68Ga-DOTATOC PET/CT in carcinoids. Pathol 
Int. 2010;60(2):143-144.  

IND # 114,398 for 68Ga-DOTATOC 
 
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22. 
Ruf J, Heuck F, Schiefer J, et al. Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy 
management in patients with neuroendocrine tumors. Neuroendocrinology. 2010;91(1):101-109.  
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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Appendix 1 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP)* 
 
 
Date:  11/12/14 
IRB#:  201110718 
Title:   Safety and Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) for Diagnosis, 
Staging, and Measurement of Response to Treatment in Somatostatin Receptor Positive 
Tumors 
PI:  M. Sue O'Dorisio, PHD, MD 
Co-I: David Bushnell, MD, Yusuf Menda, MD, Michael Schultz, PhD, Laura Ponto, PhD, John 
Sunderland, PhD, Thomas O’Dorisio, MD and Michael Graham, PhD, MD 
 
 
* All investigator-initiated protocols will be subject to ongoing monitoring of accrual, subject eligibility, 
protocol modifications and continuing reviews.  Active studies will be audited for the DSMC by the 
CRSO, following guidelines based on level of risk to subjects.  Audits will be conducted by 
reviewing subject files provided by clinical research coordinators, as well as original source 
documentation provided by online medical records and research pharmacists.  The CRSO will 
review adverse events, eligibility of subjects, and adherence to the IRB- and PRMC-approved 
protocol.  Protocols found to have discrepancies will be require a response from the PI and an 
action plan for correcting identified deficiencies.  The DSMC will provide a schedule of audit and 
report dates if requested.   
 
Type of Clinical Trial: 
 Investigator-initiated (UI/HCCC) 
 Investigator-initiated, participating site 
 Pilot study 
 Phase I 
 Phase I/II 
 Phase II 
 Phase III 
 Compassionate-use drug protocol 
 Interventional Treatment 
 Interventional Non-Treatment 
 Non-Interventional 
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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Study risk-level:  
 Level 1—low risk of morbidity or death, * <<1% of death or any adverse event  
 Level 2—risk of death* <1% or any adverse event 1% – 5%  
 Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
 Level 4—risk of death* >5% or grade 4 – 5 SAE >15%  
 Drugs being used on a “compassionate” basis  
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
Subject inclusion criteria: 
• 
Signed informed consent. 
• 
Age ≥ 2 years. 
• 
Known or suspected somatostatin receptor positive tumor such as carcinoid;  
neuroendocrine tumor; neuroblastoma; medulloblastoma; pheochromocytoma.  Supporting 
evidence may include MRI, CT, biochemical markers, and or pathology report.  
• 
Karnofsky performance status or Lansky Play Scale status of ≥ 50 (or ECOG/WHO 
equivalent). 
• 
Subject is male; or is a female who is either pre-menarchal, surgically sterile (has had a 
documented bilateral oophorectomy and/or documented hysterectomy), postmenopausal (> 
1 years without menses), non-lactating, or of childbearing potential for whom a serum 
pregnancy test (with the results known prior to investigational product administration) is 
negative. A negative serum pregnancy test will be required for all female subjects with child 
bearing potential. If a false pregnancy test is suspected, e.g., perimenopausal condition, an 
obstetrician will be consulted to determine if she is/is capable of becoming pregnant. 
• 
 
Subject exclusion criteria: 
• 
Subject weighs more than 400 pounds (Subjects who weigh more than 400 pounds will not 
be able to fit inside the imaging machines). 
• 
Inability to lie still for the entire imaging time (e.g. cough, severe arthritis, etc.) 
• 
Inability to complete the needed investigational and standard-of-care imaging examinations 
due to other reasons (severe claustrophobia, radiation phobia, etc.) 
• 
Does the subject have any additional medical condition, serious intercurrent illness, or other 
extenuating circumstance that, in the opinion of the Investigator, may significantly interfere 
with study compliance? 
• 
 
Stopping rules (subject and study): 
This is a low risk imaging protocol; the amount of radioactive peptide is below physiological effects 
level and the radiation dose is below allowable levels.  No adverse events are expected.  Adverse 
events are recorded on the CRF at the following times: 
• 
immediately following the PET/CT 
• 
at the conclusion of a 2 hrs observation time from time of injection of radiopharmaceutical 
• 
during phone call 18-24 hrs after PET/CT 
• 
one to four weeks following PET/CT at outpatient visit with physical exam and labs 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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Risks of Study Drug:   
Research radiation dose estimate: Our calculations estimate that the effective whole-body 
dose of the 68Ga-DOTATOC PET/CT is approximately 1.6 rem, less than the radiation dose 
from a conventional 18F-FDG PET/CT scan of about 2.4 rem, assuming the standard use of a 
“low-dose” CT for anatomic localization and attenuation correction, as described in our 
proposed imaging protocol. The U.S. national annual background dose for humans is 
approximately 0.36 rem.  The maximum annual permissible whole body radiation dose to a career 
radiation worker (e.g., a radiologist, nuclear medicine technologist, etc.) is 5.0 rem. Thus, the one-
time dose to the patient for the investigational PET/CT will be approximately  one-third of the annual 
permissible dose to a career radiation worker and about 5 years’ worth of background radiation in 
the US. Given the average age of the patients in this proposed investigation (about 60 years of age), 
the increased risk to the patient, who will have a known, current life-threatening malignancy, for a 
second, radiation-induced malignancy from this investigational radiation exposure is extremely low 
(estimated < 1%).  Given the risk of death from either delay in diagnosis or under-treatment of these 
known malignancies, we feel the added radiation burden to the patient is well within the patient’s 
best interest if 68Ga-DOTATOC PET/CT imaging adds value.  
 
Risks of Study Procedures  
Risks of Investigational PET/CT: An adverse reaction to the investigational radiopharmaceutical is 
possible though not reported. Additional risks include radiation exposure from the investigational 
PET/CT scan (discussed above), dosage infiltration, risks from IV access. blood tests, and the 
inconvenience of the investigational PET/CT scan. 
 
Children may require sedation or anesthesia to remain still during the PET scanning procedure.  The 
risks of sedation include a reaction to the medication used for sedation or anesthesia.  If anesthesia 
is required, there is a risk of injury to the throat or airways from insertion of the breathing tube. 
 
Risk Level 4 
Interventional treatment trials involving investigational agents or devices with a risk of death* >5% or 
grade 4 – 5 SAE >15% (all investigator initiated INDs, and most Phase I/II trials, gene therapy, gene 
manipulation or viral vector systems high-risk clinical procedures if performed solely for research 
purposes.  The use of a new chemical or drug for which there is limited or no available safety data in 
humans. 
An independent Study Monitor or the DSMC Chair (or designee), will review study data (provided by 
the PI and CRSO) and communicate with the PI at least quarterly.  A copy of this communication will 
be forwarded to the DSMC and PRMC Chairs.  This communication may coincide with the CRSO’s 
quarterly audit when possible.  If an audit has not been conducted—due to lack of research activity--
the quarterly summary letter will occur as scheduled. Subject accrual data will be obtained from 
OnCore on an ongoing basis by the CTRM during accrual review for the PRMC. 
- Subject accrual data will be obtained from OnCore on an ongoing basis by the CTRM during 
accrual review for the PRMC. 
- The research coordinator or data manager for the study will register new subjects in OnCore  
- Adverse events will be reported to the CRSO as defined in the DSMP for the study 
- Serious adverse events will be communicated to the CRSO and recorded in OnCore. 
- The CRSO will contact the research team every three months to coordinate an audit of the 
trial's research records.  Records for a minimum of 25% of subjects will be audited.  OnCore 
auditing functionality will be used to conduct, evaluate, and report on each audit. Audits will: 
o verify eligibility of patients accrued to the study, 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
30 
o check for the presence of a signed informed consent, 
o determine compliance with protocol’s study plan, 
o determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies,  
o compare accuracy of data in the research record with the primary source documents, 
o review investigational drug processing and documentation, 
o assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
 
ROUTINE ADVERSE EVENT REPORTING 
 
Table I:  Routine Reporting of Adverse Events for Phase 1 and 2 Trials 
Attribution 
Adverse Event 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Not required 
Not required 
Not 
required 
CRSO 
CRSO 
Unlikely 
Not required 
Not required 
Not 
required 
CRSO 
CRSO 
Possible 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Probable 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Definite 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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31 
EXPEDITED ADVERSE EVENT REPORTING 
 
Table II: Reporting Requirements for Adverse Events that occur within 30 Days1 of the Last Dose of the 
Investigational Agent on Phase 1 Trials 
 
1 
2 
2 
3 
3 
4 & 52 
Unexpect
ed and 
Expected 
Unexpecte
d 
Expecte
d 
Unexpected 
Expected 
Unexpected 
and Expected 
With 
Hospital 
without 
Hospital 
with Hospital 
without 
Hospital 
Unrelate
d 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Require
d 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar 
Days 
24-Hour; 5 
Calendar 
Days 
10 Calendar 
Days 
Not 
Require
d 
24-Hour; 5 
Calendar Days 
1Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 Grade 4 unexpected events 
 Grade 5 expected and unexpected events 
2Although an AdEERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
 
 
  
 

IND # 114,398 for 68Ga-DOTATOC 
 
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Appendix 2  
CRF:  
Data Collection for 68Ga-DOTATOC PET/CT  

IND # 114,398 for 68Ga-DOTATOC 
 
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SUBJECT STUDY ID:_____________  
Inclusion / Exclusion Ga-68 DOTATOC PET Protocol 
INCLUSION 
 
1. Y / N 
Signed informed consent 
 
2. Y / N 
Age > 2 years 
 
3. Y / N 
Known or suspected somatostatin receptor positive tumor such as carcinoid,  
 
 
neuroendocrine tumor, neuroblastoma, medulloblastoma or pheochromocytoma.   
 
 
Supporting evidence may include MRI, CT, biochemical markers, and / or  
 
 
pathology report 
 
4.  Y / N 
Karnofsky performance status or Lansky Play Scale status of > 50 (or  
 
 
 
ECOG/WHO equivalent) 
 
5.  Y / N 
Subject is male; or is a female who is either pre-menarchal, surgically sterile (has  
 
 
had a documented bilateral oophorectomy and/or documented hysterectomy),  
 
 
postmenopausal (> 1 years without menses), non-lactating, or of childbearing  
 
 
potential for whom a serum pregnancy test (with the results known prior to  
 
 
investigational product administration) is negative. A negative serum pregnancy  
 
 
test will be required for all female subjects with child bearing potential.  If a false  
 
 
pregnancy test is suspected, e.g., perimenopausal condition, an obstetrician will be 
 
 
consulted to determine if she is/is capable of becoming pregnant. 
 
EXCLUSION 
 
1.  Y / N 
Subject weighs more than 400 pounds.  (Subjects who weigh more than 400  
 
 
pounds will not be able to fit inside the imaging machines.) 
 
2.  Y / N 
Inability to lie still for the entire imaging time (due to cough, severe arthritis, etc.) 
 
3.  Y / N 
Inability to complete the needed investigational and standard-of-care imaging  
 
 
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.)  
 
4.  Y / N 
Does the subject have any additional medical condition, serious intercurrent  
 
 
illness, or other extenuating circumstance that, in the opinion of the investigator,  
 
 
may significantly interfere with study compliance?  
 
 
 
_________________________________________  
____________________ 
Signature of person screening 
 
 
 
Date 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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SUBJECT STUDY ID: ______________ 
Data Collection for Imaging Visit   
Subject Data (send all forms to PET Center with patient) 
1) Limited Physical Exam:  
a) HEENT (Circle or fill in blank): 
 NORMAL OR____________________________ 
b) Chest (Circle or fill in blank): 
 NORMAL OR____________________________ 
c) Cardiovascular(Circle or fill in blank): NORMAL OR____________________________ 
d) Abdomen (Circle or fill in blank):  NORMAL OR____________________________ 
e) Integument (Circle or fill in blank): 
 NORMAL OR____________________________ 
f) Musculoskeletal (Circle or fill in blank): NORMAL OR____________________________ 
g) Neurological (Circle or fill in blank): NORMAL OR____________________________ 
h) Vital: T____, P_____, BP____/_____, RR____, Height_____cm, Weight______kg 
2) Blood Drawn: Pregnancy test, CBC/diff, AST, ALT, Bilirubin, BUN, Creatinine  
  a) Time:______________ 
b) Date:_________________ 
 
3) What is the indication for the GA-68 PET/CT Exam? 
 
__Unknown primary lesion 
 
__Staging Disease 
 
__Post Therapy Staging 
4)  What is the current management plan for the 
subject?___________________________________ 
__________________________________________________________________________ 
 
 
 
Investigator (Signature)____________________________  (Date) ___________ 

IND # 114,398 for 68Ga-DOTATOC 
 
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SUBJECT STUDY ID: ______________________  
Data Collection for Imaging  
 
This page will be completed in the PET Center: 
 
 
1) Pregnancy test (urine) required? Y / N Results_________________  
 
 
2) IV inserted (location): ____________________________________  
 
3) Alprazolam Y/N     Dose __________mg @ Time _______:________  
 
 
 
a) Who is the responsible person with the subject (name)?___________________ 
 
5) Ga-68 DOTATOC Dose:  _____________mCi @ Injection Time_______:________  
6) PET Scan Start Time _________:__________  End Time__________:___________  
7) Vital Signs (supine) at PET Completion: P _____, BP ______/______, RR________  
8) Patient Observed from time of Ga-68 injection until discharged @ (time) ______:_______ 
 
Signature of PET staff: ___________________________ Date:  __________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
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SUBJECT STUDY ID:__________________ 
 
Data Collection for Follow-up Visit 
 
 
Vitals:  T____, P____ BP____/_____, RR____, Weight______kg 
 
Blood Draw: CBC w/diff, AST, ALT, Bilirubin, BUN, Creatinine, @ Time:_________________ 
 
AE Questionnaire to be completed for any reactions to the Ga-PET in the last week. 
 
Any new con-meds in the last week:  Yes ____  No ____ 
 
 
 
If Yes, please specify: __________________________________________________ 
 
 
 
Signature and Date:________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
37 
SUBJECT STUDY ID:__________________ 
 
Ga-68 DOTATOC PET Adverse Event Questionnaire 
Please only list AEs that are new and have happened since the Ga-PET scan. 
POSSIBLE ADVERSE EVENTS 
YES/NO 
COMMENTS/NOTES 
BODY AS A WHOLE 
Pain (abdominal) 
Pain (chest/breast) 
Pain (other/site) 
Fever 
Injection site reaction 
  
CARDIOVASCULAR SYSTEM 
Flushing (vasodilatation) 
DIGESTIVE SYSTEM 
Nausea 
Diarrhea 
Vomiting 
  
RESPIRATORY SYSTEM 
Dyspnea (shortness of breath) 
SKIN & APPENDAGES 
Rash 
Itching (pruritus) 
Hives (urticaria) 
Sweating 
Cyanosis (finger or toe 
discoloration) 
  
  
  
CENTRAL NERVOUS SYSTEM 
Visual disturbances 
Numbness of feet 
Numbness of fingers/hands 
Weakness of feet 
Weakness of fingers 
Burning sensation in feet 
Burning sensation in fingers 
  
 
 
Signature:___________________________ Date:________________ Time:____________ 
 

IND # 114,398 for 68Ga-DOTATOC 
 
O’Dorisio, M Sue 
 
38 
SUBJECT STUDY ID:__________________ 
 
Karnofsky Performance Scale 
 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
 
Able to carry on normal activity and to work; no special 
care needed 
100 Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
Unable to work; able to live at home and care for most 
personal needs; varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Required occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Required considerable assistance and 
frequent medical care. 
Unable to care for self; required equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; required special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
  
  
 
 
 
 
Signature:___________________________ Date:________________ Time:____________