Trial Information

Safety and Efficacy of 68Ga-DOTA-tyr3-Octreotide PET/CT in Diagnosis, Staging and Measurement of Response to Treatment in Patients With Somatostatin Receptor Positive Tumors: Comparison to Octreoscan Plus High-Resolution, Contrast Enhanced CT.

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

The purpose of this amendment 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.