Safety of 68Ga-DOTA-tyr3-Octreotide PET in Diagnosis of Solid Tumors

This protocol is designed to test the efficacy of 68Ga-DOTATOC PET/CT in diagnosis, staging,
and measurement of response to treatment in patients with somatostatin receptor positive
tumors. The goals are to 1) compare this unique PET/CT scan with the current standard of care
which is a combination of Octreoscan SPECT (single photon emission tomography) plus a high
resolution, contrast enhanced CT; 2) Determine the sensitivity of 68Ga-DOTATOC PET/CT in
diagnosis of patients with suspected somatostatin receptor positive tumor; and 3) For those
patients who have had recent treatment (e.g., surgery, chemotherapy, targeted therapy such as
anti-angiogenics, kinase inhibitors, peptide receptor radiotherapy), this scan will be used
to measure response to treatment. These studies will be obtained with the long term goal of
submitting a New Drug Application (NDA) for FDA approval of 68Ga-DOTATOC PET/CT in adults and
children.

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 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.

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.

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
diagnosis[1]. Other tumors that express high levels of somatostatin receptors include
neuroblastoma, medulloblastoma, and Ewing's sarcoma[2-4].

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 disease[5]. 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 years[6-8].

Somatostatin Receptor Targeted Imaging and Therapy

Tumors that express somatostatin receptors can be targeted with radiolabeled somatostatin
analogues for imaging and treatment. 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 sstr2[9].

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
analogues[10]. 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.

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 sstr5[14]. 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 tumors[15].

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. These investigators have conducted a single institution Phase I trial of 90Y-DOTATOC
therapy in children and young adults (Appendix I) and have participated in a Phase II trial
of 90Y-DOTATOC PRRT in adults (also in Appendix II).

The purpose of this amendment to the IND application is to test the efficacy of
68Gallium-DOTATOC in diagnosis, staging, and determination of response to 90Y-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.

Inclusion Criteria:

- Signed informed consent

- Age greater than or equal to 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 greater than 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?