Comparator Study of 68Ga-DOTATOC PET/CT With Octreoscan + High-resolution, Contrast-enhanced CT for Diagnosis and Staging in Neuroendocrine Tumors and Other Somatostatin Receptor Positive Tumors
Phase: PHASE2
Conditions: Adult Medulloblastoma, Childhood Medulloblastoma, Neuroblastoma, Neuroendocrine Tumor, Somatostatinoma
Sponsor: Sue O'Dorisio

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
1 
 
 
 
 
 
 
 
Comparator Study of 68Ga-DOTATOC PET/CT with Octreoscan + high-
resolution, contrast-enhanced CT for diagnosis and staging in 
neuroendocrine tumors and other somatostatin receptor positive tumors 
 
 
 
Principal Investigator:  M. Sue O’Dorisio, MD, PhD 
Co-principal Investigator:  Yusuf Menda, MD 
 
Co-Investigators: 
Thomas O’Dorisio, MD 
Gideon Zamba, PhD 
David Bushnell, MD 
Chenue Abongwa, MD 
Michael Schultz, PhD 
David Dick, PhD 
Laura Ponto, PhD 
John Sunderland, PhD 
Michael Graham, PhD, MD 
 
Document type: PROTOCOL FOR RO1 CA 167632 
IND# 114,398 
IRB# 201212736 
Version number: 9 
Date: March 26, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
2 
 
 
Comparator Study of 68Ga-DOTATOC PET/CT with Octreoscan + high-
resolution, contrast-enhanced CT for diagnosis and staging in 
neuroendocrine tumors and other somatostatin receptor positive tumors 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. Introduction…………………………………………………………. 3 
2. General Investigational Plan……………………………………… 6  
3. Clinical Protocol……………………………………………………. 6 
4. Chemistry, Manufacturing and Control………………………….. 15 
5. Labeling…………………………………………………………….. 17 
6. Pharmacology and Toxicology…………………………………… 17 
7. Previous Human Experience …………………………………….. 17 
8. References………………………………………………………..... 21 
 
 
Appendices: CRFs  attached as separate file in HawkIRB 
 
I. 
Sample Case Report Forms 
II. 
Data Safety Monitoring Plan 
 
 
Summary of Changes to version 9 dated 3/26/14 
Title page  
Updated version and date 
Table of Content 
Updated  page numbers 
Safety section protocol and DSMP 
Updated to current HCCC DSMC risk level 2 
language 
 
 
 
 
 
 
 
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
3 
 
Project Goal 
Compare Sensitivity and specificity of 68Ga-DOTATOC PET/CT with Octreoscan + high-
resolution, contrast-enhanced CT for diagnosis and staging in neuroendocrine tumors 
and other somatostatin receptor positive 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  
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. 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
4 
Tumors that express somatostatin receptors can be targeted with radiolabeled somatostatin analogues 
for imaging and treatment (Figure 1). Somatostatin receptor gamma camera imaging with 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 68Ga-DOTA-conjugated peptides have been introduced, including 68Ga-DOTA0-
Tyr3]octreotide (68Ga-DOTATOC), Ga-68 DOTA0-1NaI3-octreotide (68Ga-DOTANOC) and 68Ga- 
DOTA0-Tyr3]octreotate (68Ga-DOTATATE). 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 quantification of uptake due to robust attenuation correction. The improved resolution and 
quantitation of uptake obtained with 68Ga-DOTATOC PET/CT should provide a more accurate 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
5 
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 68Ga-DOTATOC PET/CT 
with Octreoscan found 68Ga-DOTATOC PET/CT to be superior in detection of skeletal and pulmonary 
involvement of neuroendocrine tumors15.   We have recently published an analysis of the reproducibility of 
sequential 68Ga-DOTATOC PET/CT imaging in patients with known neuroendocrine tumors16 
 2.  Rationale and overall study design 
Rationale: 
The purpose of this clinical trial is to compare the efficacy of 68Ga-DOTATOC PET/CT in diagnosis and 
staging of somatostatin receptor positive tumors, including, but not limited to neuroendocrine tumors, 
neuroblastoma, and medulloblastoma, with the current standard of care in the United States, namely, an 
Octreoscan + a high-resolution, contrast-enhanced CT.  
 
If efficacy of 68Ga-DOTATOC PET imaging is equivalent or superior, it would replace  single photon 
emission tomography (SPECT) imaging with Octreoscan over which it has known advantages.  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 68Ga-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 compare efficacy of [68Ga]-DOTA-tyr3-Octreotide (68Ga-DOTATOC) PET/CT 
with Octreoscan + high-resolution, contrast-enhanced CT for diagnosis and staging in patients with 
somatostatin receptor expressing tumors. 
 
Project Design 
This is a prospective, single center, open-label study in subjects with known neuroendocrine tumors and 
other Somatostatin receptor positive tumors to evaluate the accuracy of 68Ga-DOTATOC PET-CT 
Eligible participants will have an Octreoscan and a high-resolution contrast-enhanced CT within 120 days 
(+/- 12 days to allow for scheduling conflicts and travel) of the 68Ga-DOTATOC PET-CT.  All subjects will 
undergo baseline assessments at enrollment. Study participants will receive 68Ga-DOTATOC and 
undergo a PET/CT imaging study. A second 68Ga- DOTATOC PET-CT will be obtained in patients if the 
lesions of the first scan cannot be confirmed with histology and/or other imaging modalities. 
 
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.  The study will be posted on 
clinicaltrials.gov as another recruitment option. 
Schema 
 
Informed Consent 
   
Review pathology report, Octreoscan, CT, and laboratory tests 
Physical exam with vital signs 
Blood tests (CBC, differential, AST, ALT, bilirubin, BUN, creatinine) 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
6 
Pregnancy test if indicated 
Injection of 68Ga-DOTATOC 
PET/CT scan 
vital signs 
 
Phone call follow-up 18-36 hrs after PET/CT 
 
Repeat blood tests (AST, ALT, bilirubin, BUN, creatinine) within 7 days after PET/CT scan 
 
Patients may undergo second scan 3-6 months (+/- 18 days to allow for scheduling conflicts and travel) 
after first 68Ga-DOTATOCPET/CT scan using above schedule. 
 
 2.  Clinical Protocol 
Inclusion Criteria:  
 
• 
Signed informed consent. 
• 
Age ≥ 2 years. 
• 
Biopsy proven neuroendocrine tumor, neuroblastoma, medulloblastoma, or other somatostatin 
receptor positive tumor.     
• 
Off Sandostatin-LAR >4 weeks and off immediate release (subcutaneous) for 12 hrs prior to 68Ga-
DOTATOC PET-CT. 
• 
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. 
• 
No therapy other than Sandostatin since last Octreoscan + diagnostic CT;  
• 
Fresh frozen (recommended) or paraffin fixed (required) specimen of primary or metastases 
available for RNA and IHC;  
Exclusion Criteria: 
• 
Pregnancy or breast feeding  
• 
Surgical resection, chemotherapy, radiation therapy, or biologic therapy since last Octreoscan + 
CT.  Continuation of the same dose of Sandostatin–LAR or subcutaneous Sandostatin is allowed. 
• 
Medical condition uncontrolled by treatment making completion of study unlikely. 
• 
Weight 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.) 
• 
Any additional medical condition, serious intercurrent illness, or other extenuating circumstance 
that, in the opinion of the Investigator, may significantly interfere with study compliance 
 
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.  

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
7 
 
Table 1.  Schedule of Study Events 
 
Visit 1a  
(-30 to -1 
day)  
Scan 
1b 
1-7 
days 
Scan     
2 
1-7 
days  
Informed consent  
X 
 
 
 
 
Medical history 
X 
 
 
X 
 
Physical examination 
Xc 
X 
 
X 
 
Concomitant meds 
X 
X 
 
X 
 
Blood pressure, temp, 
respiratory rate, heart rate, 
weight 
X 
X 
 
X 
 
CBC, differential 
 
X 
 
X 
 
, 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 
Octreoscan and contrast CT (or MRI) within 120 days of Ga-68 DOTATOC 
PET/CT 
a Screening visit occurs within 30 days of Ga-68 DOTATOC PET/CT 
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. 
 
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).  
 
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 (Appendix IV). 
 
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 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 Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
8 
68Ga-DOTATOC PET/CT Scan 
Study participants will undergo the 68Ga-DOTATOC PET/CT after all screening and baseline 
assessments have been completed. The dose 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.  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. 
 
Interpretation discrepancies 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 or recovery room 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. Subjects will be required to have repeat blood tests within 1 week of the PET/CT. 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 any 
other clinical information prior to initial interpretation.  A board certified nuclear medicine physician, 
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 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 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 

6 8 G a -D O T A T O C  C o m p ar at or St u d y  
I N D # 1 1 4, 3 9 8  
 
O’ D ori si o, M S u e  
 
9 
tr e at m e nt d e ci si o n s. T h e s e r e s ult s will b e r e c or d e d f or st ati sti c al a n al y si s. Aft er t h e i n v e sti g ati o n al 6 8 G a -
D O T A T O C P E T/ C T h a s b e e n i n d e p e n d e ntl y i nt er pr et e d, c o m p ari s o n will b e m a d e wit h ot h er, 
c o n v e nti o n al i m a gi n g ( CI), a s a v ail a bl e. CI u s e d f or c o m p ari s o n will i n cl u d e C T s c a n s, M RI s c a n s, 
O ctr e o s c a n s, ultr a s o u n d s a n d x -r a y pl ai n fil m s. P art of d at a a n al y si s s p e cifi c t o i m a gi n g will i n cl u d e:  
W h et h er t h er e w er e sit e s of t u m or s e e n wit h 6 8 G a -D O T A T O C P E T/ C T n ot s e e n wit h CI, a n d, if s o, t h e s e 
d at a will b e r e c or d e d f or st ati sti c al a n al y si s   W h et h er or n ot t h e 6 8 G a -D O T A T O C P E T/ C T r e s ult e d i n a 
c h a n g e i n st a g e  r el ati v e t o CI, a n d, if s o, w h et h er it w o ul d b e u p- v s. d o w n - st a gi n g   W h et h er or n ot t h e 
6 8 G a -D O T A T O C P E T/ C T s c a n r e s ult c a u s e d t h e cli ni c al c ar e  gi v er s t o c h a n g e tr e at m e nt, e. g. c h a n g e 
wit hi n m o d alit y ( e. g. c h a n g e  S a n d o st ati n d o s e, r e q u e st s ur g er y c o n s ult) or a cr o s s m o d aliti e s ( e. g. a d d  
c h e m ot h er a p y or r a di ati o n t h er a p y t o s ur g er y, et c.).  
 
D at a A n al y si s:  
 
6 8 G a -D O T A T O C P E T s c a n s will b e c o m p ar e d t o a c o m p o sit e g ol d -st a n d ar d t h at i n cl u d e s c o n v e nti o n al 
i m a gi n g m o d aliti e s a n d cli ni c al f oll o w-u p t o d et er mi n e t h e s e n siti vit y a n d s p e cifi cit y of 6 8 G a -D O T A T O C 
P E T:  
 
A l e si o n vi s u a li z e d o n  6 8 G a-D O T A T O C P E T/ C T will b e c o n si d er e d a s tr u e p o siti v e if  
1 ) pr o v e n b y bi o p s y O R  
2) vi s u ali z e d o n b a s eli n e O ctr e o s c a n A N D di a g n o sti c C T s c a n  O R  
3) v i s u ali z e d o n O ctr e o s c a n O R di a g n o sti c C T A N D c o n c or d a nt N E T bi o m ar k er s ar e p o siti v e O R  
4) 6 8 G a -D O T A T O C P E T p o siti v e b o n e l e si o n n ot vi s u ali z e d o n O ctr e o s c a n O R di a g n o sti c C T i s cl e arl y 
vi si bl e o n b o n e s c a n or M RI O R  
5) 6 8 G a -D O T A T O C P E T p o siti v e l e si o n n ot pr o v e n wit h 1 t o 4 a b o v e s h o w s i n cr e a s e i n 6 8 G a -D O T A T O C 
P E T/ C T o n a 3- 6- m o nt h f oll o w -u p s c a n ( +/- 1 8 d a y s t o all o w f or s c h e d uli n g c o nfli ct s a n d tr a v el) wit h 
c o n c or d a nt N E T bi o m ar k er s. If a 6 8 G a -D O T A T O C p o siti v e l e si o n c a n n ot b e c o nfir m e d wit h a n y of t h e s e 
fi v e p ar a m et er s, it will b e c o n si d er e d f al s e-p o siti v e.  
 
A n e g ati v e 6 8 G a -D O T A T O C P E T/ C T will b e c o n si d er e d tr u e n e g ati v e if n o l e si o n s ar e f o u n d o n 
O ctr e o s c a n A N D di a g n o sti c C T a n d N E T t u m or bi o m ar k er s  ar e n e g ati v e. A n e g ati v e 6 8 G a -D O T A T O C 
P E T/ C T will b e c o n si d er e d f al s e n e g ati v e if : 
1) a c o n c or d a nt l e si o n i s f o u n d o n O ctr e o s c a n  a n d di a g n o sti c C T at b a s eli n e O R  
2) a N E T l e si o n i s c o nfir m e d b y p at h ol o g y O R  
3) a l e si o n i s i d e ntifi e d o n di a g n o sti c C T wit h c o n c or d a nt bi o m ar k er s or s h o w s i nt er v al gr o wt h o n f oll o w u p 
C T O R  
4) o s s e o u s m et a st a s e s ar e i d e ntifi e d o n M RI or b o n e s c a n.  
 
R e c e pt or a n al y si s  
Ti s s u e s o bt ai n e d f or t h e p ati e nt s will b e a n al y z e d f or t h e pr e s e n c e of s o m at o st ati n r e c e pt or 2 b y 
i m m u n o hi st o c h e mi str y a n d/or R T -P C R. P o siti vit y a n d gr a d e will b e d et er mi n e d b y a b o ar d -c ertifi e d 
p at h ol o gi st. T h e s e r e s ult s will b e c orr el at e d wit h t h e si g n al i nt e n sit y f or t h e 6 8 G a -D O T A T O C P E T/ C T.  
 
St ati sti c al C o n si d er ati o n s  
T h e  di stri b uti o n of p ati e nt s will b e a n  i m p ort a nt el e m e nt of st ati sti c al c o n si d er ati o n. S e v er al t y p e s of 
p ati e nt s will b e st u di e d, i n cl u di n g  p ati e nt s wit h:  
•  
Pri m ar y  p a n cr e ati c , s m all b o w el, or l u n g n e ur o e n d o cri n e t u m or 
•  
M et a st ati c p a n cr e ati c , s m all b o w el or l u n g n e ur o e n d o cri n e t u m or 
•  
Pri m ar y or m et a st ati c n e ur o bl a st o m a  
•  
Pri m ar y or m et a st ati c m e d ull o bl a st o m a  
•  
Pri m ar y or m et a st ati c p h e o c hr o m o c yt o m a  
Gi v e n t h e di stri b uti o n o f p ati e nt s s e e n at t h e U ni v er sit y of I o w a  H o s pit al s , a n e x c ell e nt di stri b uti o n of 
p ati e nt s will b e e nr oll e d. W e  pr e di ct t h at wit h a t ot al of  1 1 2  s u bj e ct s, e a c h of t h e a b o v e t y p e s of 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
10 
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 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%. 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
11 
 
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 
 
 
Risks 
Risks of Study Drug 
Research radiation dose estimate:  The effective whole-body dose of the 68Ga-DOTATOC PET/CT is 
approximately 1.6 rem17, 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. 
 
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 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
12 
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. 
 
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 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
13 
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 
requirements. SAEs should be followed to resolution, even if this is after the study reporting period.  
 
Data and Safety Monitoring 
The Data Safety Monitoring Plan for this study (see Appendix II) is written to ensure the safety of subjects 
and to verify the validity and integrity of the data. 
 
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).” 
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 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
14 
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.  
 
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.   
 
For information about Adverse Event reporting to the CRSO/DSMC, refer to Data and Safety Monitoring 
Plan for this study (Appendix II).  
 
Study Withdrawal/Discontinuation 
This is a low risk imaging protocol; the amount of physiologically active 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: 
 
 
 
after injection of radiopharmaceutical and before discharge from the PET Center following imaging 
 
during phone call 18-24 hrs after PET/CT 
 
 
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. 
 
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, 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
15 
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 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 IV), 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 and accepted or rejected.  Accepted reagents are labeled with 
appropriate expiration dates, initialed, assigned identification numbers and quarantined in specified 
locations in the radiopharmaceutical laboratory. The University of Iowa (UI) PET Center 
Radiopharmaceutical Laboratory is staffed with expert radiochemists who oversee the preparation of the 
radiopharmaceuticals and are experienced in the compounding of the proposed investigational 
radiopharmaceutical because of its ongoing use under IND # 114,398.  
 
Because Ga-68 has a 68 minute half life, production of 68Ga-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-6818. 
 
According to the 68Ga-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 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
16 
(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 preparation19. 
 
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 release20,21.  
 
The solution is 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 68Ga-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 vial22.  
 
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  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, 68Ga-DOTATOC, and free Ga-68 can be 
differentiated at rf – 0.0, 0.5 and 1.0, respectively.  
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
17 
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 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. 
 
5. Labeling 
Each unit dose will be made at the time of use 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 Positron 
Emission Tomography in Patients with Somatostatin Receptor Positive Tumors:  A Feasibility Study”16 
(Appendix III). 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 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
18 
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 organ. Percentage error (i.e. reproducibility) was calculated for 
each lesion as Percentage Error = 100*ABS (Scan 2-Scan 1)/((Scan 2 + Scan 1)/2))23.       *mean + standard deviation 
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
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Production of 68Ga-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, radionuclidic, sterility as shown in Table 4. 
 
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 SPECT24. Although we have successfully employed 
[111In]DTPA-octreotide SPECT/CT (Octreoscan) + a diagnostic CT for diagnosis, staging, and monitoring 
of NET in children and adults2,25, 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 tumors26-28. Several advantages of 
68Ga-DOTATOC PET/CT have been pointed out through these published studies. For example, Gabriel 
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).  

68Ga-DOTATOC Comparator Study 
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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 States29.  
 
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 NETs26-28. 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 
research29. 
 
 
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
21 
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. 
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. 
Menda Y, Boles Ponto LL, Schultz MK, et al. Repeatability of Ga-68 DOTATOC PET Imaging in 
Neuroendocrine Tumors. Pancreas. 2012;In Press. 
17. 
Hartmann H, Zophel K, Freudenberg R, et al. [Radiation exposure of patients during 68Ga-
DOTATOC PET/CT examinations]. Nuklearmedizin. 2009;48(5):201-207.  
18. 
Velikyan I. Positron emitting [68Ga]Ga-based imaging agents: chemistry and diversity. Med Chem. 
2011;7(5):345-379.  
19. 
Ocak M, Antretter M, Knopp R, et al. Full automation of (68)Ga labelling of DOTA-peptides 
including cation exchange prepurification. Appl Radiat Isot. 2010;68(2):297-302.  
20. 
Capello A, Krenning EP, Breeman WA, Bernard BF, Konijnenberg MW, de JM. Tyr3-octreotide and 
Tyr3-octreotate radiolabeled with 177Lu or 90Y: peptide receptor radionuclide therapy results in vitro. 
Cancer BiotherRadiopharm. 2003;18(5):761-768. 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
O’Dorisio, M Sue 
 
22 
21. 
Breeman WA, de JM, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of 
DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. EurJNuclMedMolImaging. 
2003;30(6):917-920. 
22. 
de Jong M, Breeman WA, Valkema R, Bernard BF, Krenning EP. Combination radionuclide 
therapy using 177Lu- and 90Y-labeled somatostatin analogs. JNuclMed. 2005;46 Suppl 1:13S-17S. 
23. 
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.  
24. 
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. 
25. 
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. 
26. 
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. 
27. 
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 MePrepublished on 2010/12/24 as DOI 
10.3904/kjim.2010.25.4.386. 
28. 
Jindal T, Kumar A, Kumar R, Dutta R. Role of 68Ga-DOTATOC PET/CT in carcinoids. Pathol Int. 
2010;60(2):143-144.  
29. 
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.  
 
 
 
 

68Ga-DOTATOC Comparator Study 
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23 
Appendix II: Data and Safety Monitoring Plan 
 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP) 
 
Date: 2/24/15 
IRB#:  20122736   IND# 114,398 
Study Title: Comparator Study of 68Ga-DOTATOC PET/CT with Octreoscan + high-resolution, contrast-
enhanced CT for diagnosis and staging in neuroendocrine tumors and other somatostatin receptor 
positive tumors 
Principal Investigator:  M. Sue O’Dorisio, MD, PhD 
Co-Investigators:  Yusuf Menda, MD, Thomas ODorisio, MD, Joseph Dillon, MD,  Blanca Schafer, MS, 
and Mary Schall, BSN 
 
All investigator-initiated protocols will be subject to ongoing monitoring of accrual, subject eligibility, 
protocol modifications and continuing reviews.   
 
 
Type of Clinical Trial (check all that apply): 
__X___ Investigator-initiated (Iowa) 
_____ Investigator-initiated, multi-center (non-Iowa) 
• 
Is this study monitored by an outside DSMB?   Yes_____  No_____ 
_____ Compassionate-use drug protocol 
_____ Pilot study 
_____ Phase I 
_____ Phase I/II 
_____ Phase II 
_____ Phase III 
_____ Phase IV 
 
 
 
 
 

68Ga-DOTATOC Comparator Study 
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O’Dorisio, M Sue 
 
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Study risk-level (refer to attached risk-level assessment for this study):  
_____ Level 1—low risk of morbidity or death, * <<1% of death or any adverse event  
X         Imaging Study_ 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 
 
Risk Level 2 
Interventional trials with a risk of death* <1% or any adverse event 1% – 5%, i.e. behavioral 
interventions, nutritional therapies, low risk procedures (e.g., endoscopy, glucose-tolerance 
tests, induced sputum, skin or muscle biopsy, nasal wash, lumbar puncture, bone marrow 
biopsy, imaging requiring sedation), as well as therapeutic trials involving agents with known 
safety profiles already licensed for the indication and age group.  Most disease-prevention 
trials will be considered at least a Risk Level 2.  
Study Safety Review: The PI or designated study personnel will review all data, including 
completeness of study data, enrollment, protocol deviations, drop-outs, adverse events on a 
regular basis and provide an annual report to the DSMC and 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 entered directly into an OnCore SAE 
report by the research team.  OnCore will send an automatic 
notification to the PI, DSMC Chair/acting Chair, CRSO, and CTRM.  
Tables I below provide CRSO reporting guidelines. 
Routine Adverse Event Reporting 
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. The PI or designated study personnel will review all data, 
including completeness of study data, enrollment, protocol deviations, drop-outs, adverse events on a 
regular basis and provide an annual report to the DSMC and PRMC.  
 
The CRSO will be responsible for collecting and collating the appropriate data provided by the PI for the 
DSMC. As part of the ongoing monitoring of this study, the PI will maintain an AE summary table and a 
protocol deviation log. 
 
Routine reporting of adverse events for PI-initiated trials to the DSMC via the CRSO is described in    
Table 1: 

68Ga-DOTATOC Comparator Study 
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O’Dorisio, M Sue 
 
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Table I:  Routine Reporting of Adverse Events for PI-initiated Trials 
Attribution 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Not required 
Not required 
Not required 
Not required 
CRSO 
Unlikely 
Not required 
Not required 
Not required 
Not required 
CRSO 
Possible 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Probable 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Definite 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
 
 
Table II: Expedited Adverse Event Reporting 
 
IND Studies:  Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND 
within 30 Days of the Last Administration of the Investigational Agent/Intervention. 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse 
Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported 
to the sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Time frames 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
10 Calendar 
Days 
 
 
 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not 
required 

68Ga-DOTATOC Comparator Study 
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O’Dorisio, M Sue 
 
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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) Part of the CAEPR. 
Expedited AE reporting timelines are defined as: 
 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
within 10 calendar days of learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or 
definite require reporting as follows: Expedited 24-hour notification followed by 
complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
NOTE: Deaths clearly due to progressive disease should NOT be reported expeditiously but 
rather should be reported via routine reporting methods. 
 
 
** For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated 
hospitalization (or prolongation of existing hospitalization) must be reported regardless of requirements 
for Phase of study, expected or unexpected and attribution. 
 
 
 

68Ga-DOTATOC Comparator Study 
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Eligibility  
 
Inclusion Criteria:  
 
• 
Signed informed consent. 
• 
Age ≥ 2 years. 
• 
Biopsy proven neuroendocrine tumor, neuroblastoma, medulloblastoma, or other somatostatin 
receptor positive tumor.     
• 
Off Sandostatin-LAR >4 weeks and off immediate release (subcutaneous) for 12 hrs prior to 68Ga-
DOTATOC PET-CT. 
• 
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. 
• 
No therapy other than Sandostatin since last Octreoscan + diagnostic CT;  
• 
Fresh frozen (recommended) or paraffin fixed (required) specimen of primary or metastases 
available for RNA and IHC;  
 
 
Exclusion Criteria: 
• 
Pregnancy or breast feeding  
• 
Surgical resection, chemotherapy, radiation therapy, or biologic therapy since last Octreoscan + 
CT.  Continuation of the same dose of Sandostatin–LAR or subcutaneous Sandostatin is allowed. 
• 
Medical condition uncontrolled by treatment making completion of study unlikely. 
• 
Weight 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.) 
• 
Any additional medical condition, serious intercurrent illness, or other extenuating circumstance 
that, in the opinion of the Investigator, may significantly interfere with study compliance 
 
 

68Ga-DOTATOC Comparator Study 
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Stopping Rules 
Study Withdrawal/Discontinuation 
This is a low risk imaging protocol; the amount of physiologically active 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 
 
Within one week following PET/CT at outpatient visit with blood tests 
 
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. 
 
 
 

68Ga-DOTATOC Comparator Study 
IND # 114,398  
 
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Toxicities  
 
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. 
 
Radiation Risk 
The maximum amount of radiation from the research-related radiation procedures in this study is 
equivalent to approximately 60 % of the annual radiation limit for a medical worker. This does not include 
the radiation you received with your last Octreoscan and high-resolution, contrast-enhanced CT. Although 
there are no proven harmful effects from this amount of radiation, long term effects on your health such as 
cancer cannot be ruled out with certainty.  This dose estimate takes into account only the exposure to 
research procedures in this project.   If you have participated in other research studies involving radiation 
exposure, you should be aware that the risk of effects from radiation is believed to increase with each 
exposure you receive, including studies performed as part of your medical care. 
 
PET Scan Risk 
The PET/CT scanner is a large machine with a hollow tube, open on both ends, that which will be used to 
see how much 68Ga-DOTATOC is taken into your tumor. You will be asked to lie on your back on a 
special table that slides into the tube.  The sides of the tube will be fairly close to your body and you will 
be in this scanner for approximately 15-35 minutes.  You will be able to talk to people in the room through 
a speaker system.  We will monitor you closely while you are inside the scanner. The risks from the PET 
scan include the radiation described above, pain from lying still on the table or a panic attack if you have 
claustrophobia. 
 
Women Capable of Becoming Pregnant 
If you are a woman who is capable of becoming pregnant, we will ask you to have a pregnancy test 
before beginning this study. You must tell us if you may have become pregnant within the previous 14 
days because the pregnancy test is unreliable during that time. You must use effective birth control 
methods and try not to become pregnant while participating in this study.  If you become pregnant, there 
may be unknown risks to your fetus, or risks to your fetus that we did not anticipate, associated with being 
in the study. There may be long-term effects of the treatment being studied that could increase the risk of 
harm to an unborn child.  If you believe or know you have become pregnant while participating in this 
research study, please contact Dr. MS O’Dorisio at 319-356-3595 as soon as possible so that counseling 
can be provided to you. 
 
Radiation Exposure in Women Who are Breast Feeding 
You may not participate in this study if you are breast feeding an infant.  There is a chance that the 68Ga-
DOTATOC could travel to your infant in your breast milk and cause unknown risks to your child.