Image-guided Diagnosis and Therapy of Neuroendocrine Tumors

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DESCRIPTION (provided by applicant): Image-guided, molecularly-targeted peptide receptor radio-therapy (PRRT) provides superior response rates in patients with neuroendocrine tumors (NETs) compared to any treatments currently available; yet, it is not available for patients in the United States. Our proposal seeks to remedy this situation by developing standardized methods for [68Ga]DOTATOC PET/CT and for dosimetry-guided PRRT using [90Y]DOTATOC. INDs generated for initial clinical trials will be made freely available through the Society of Nuclear Medicine Clinical Trials Network, leading to submission of New Drug Applications (NDA) by our industry partners, Eckert-Zeigler (EZ) and Molecular Insight Pharmaceuticals (MIP). The end result will be to make [68Ga]DOTATOC PET/CT and [90Y]DOTATOC PRRT widely available in the US for patients with NETs. NET incidence has increased 5-fold over the last 30 years, but there is currently no curative treatment for the majority of these patients. Surgery can be curative in patients who are diagnosed early, but is limited by the fact that 80% of patients have inoperable metastases at diagnosis, with a 5-year survival rate <30%. Our preliminary data showing the first [68Ga]DOTATOC PET/CTs in the US, demonstrate superior imaging sensitivity and specificity compared to FDA approved Octreoscan for detection of primary and metastatic lesions. These findings strongly support our proposal to translate combined functional and anatomical imaging using [68Ga]DOTATOC PET/CT to the clinical arena for diagnosis, staging, and quantitative measurement of response to therapy in patients with NETs. 68Ga has advantages for clinical use because it can provide PET resolution without the need for a cyclotron; however, concerns about manufacturer ability to provide generator technology meeting regulatory compliance has slowed FDA acceptance in the US. Our strong preliminary data generated with GMP DOTATOC (MIP) and a gallium generator (EZ), demonstrate that [68Ga]DOTATOC can now be reliably prepared using disposable GMP compliant cassette-based kits (EZ), thereby making clinical [68Ga]DOTATOC possible within the framework of US regulatory requirements. No controlled trials have examined the potential of quantitative measurement of response to therapy using [68Ga]DOTATOC and no study has combined these efforts in a multisite prospective standardized trial that could advance these patient care regimens to widespread acceptance in the US. According to the definition of innovation in PAR-10-169, the proposed research is innovative because it develops an optimized and standardized proposal for image-guided PRRT using [68Ga]DOTATOC PET/CT for diagnosis, staging, and selection of patients that can benefit most from [90Y]DOTATOC therapy. This contribution is significant because it will identify the effects of radiopharmaceutical formulation characteristics on the relative effectiveness of the [68Ga]DOTATOC and [90Y]DOTATOC drug products, and will also result in a standardized platform to accelerate translation of PRRT to multi-institutiona clinical trials that will be required for widespread availability in the US. We know of no other Academic-Industry partnership that is capable of bringing [68Ga]DOTATOC PET/CT image-guided [90Y]DOTATOC therapy to the US for patients with NETs.