Image-guided Diagnosis and Therapy of Neuroendocrine Tumors

描述（由申请人提供）：与目前可用的任何治疗相比，图像引导的分子靶向肽受体放射治疗（PRRT）在神经内分泌肿瘤（NET）患者中提供了上级缓解率;然而，它不适用于 美国的我们的提案旨在通过开发[68 Ga]DOTATOC PET/CT和使用[90 Y]DOTATOC进行剂量测定指导的PRRT的标准化方法来纠正这种情况。初步临床试验产生的IND将通过核医学临床试验网络协会免费提供，导致我们的行业合作伙伴Eckert-Zeigler（EZ）和Molecular Insight Pharmaceuticals（MIP）提交新药申请（NDA）。最终结果将是使[68 Ga]DOTATOC PET/CT和[90 Y]DOTATOC PRRT在美国广泛用于NET患者。 在过去的30年中，NET的发病率增加了5倍，但目前对大多数患者没有治愈性治疗。早期诊断的患者可以手术治疗，但80%的患者在诊断时有不可手术的转移，5年生存率<30%。 我们的初步数据显示，美国第一台[68 Ga]DOTATOC PET/CT与FDA批准的Octreoscan相比，在检测原发性和转移性病变方面具有更高的上级成像灵敏度和特异性。这些发现有力地支持了我们的建议，即将使用[68 Ga]DOTATOC PET/CT的功能和解剖成像结合起来，应用于临床竞技场，用于诊断、分期和定量测量NET患者对治疗的反应。68 Ga在临床应用中具有优势，因为它可以提供PET分辨率而无需回旋加速器;然而，对制造商提供符合法规合规性的发生器技术的能力的担忧减缓了美国FDA的接受。我们使用GMP DOTATOC（MIP）和镓发生器（EZ）生成的强有力的初步数据表明，[68 Ga]DOTATOC现在可以使用一次性GMP合规盒基试剂盒（EZ）可靠地制备，从而使临床[68 Ga]DOTATOC在美国监管要求的框架内成为可能。 没有对照试验研究了使用[68 Ga]DOTATOC定量测量治疗反应的潜力，也没有研究将这些努力结合在多中心前瞻性标准化试验中，可以将这些患者护理方案推广到美国的广泛接受。根据PAR-10-169中创新的定义，拟议的研究具有创新性，因为它开发了一种优化和标准化的图像引导PRRT建议，使用[68 Ga]DOTATOC PET/CT进行诊断，分期和选择可以从[90 Y]DOTATOC治疗中获益最多的患者。这一贡献是重要的，因为它将确定放射性药物配方特性的影响 关于[68 Ga]DOTATOC和[90 Y]DOTATOC药物产品的相对有效性，还将产生一个标准化平台，以加速PRRT向多机构临床试验的转化，这将是在美国广泛使用所需的。据我们所知，没有其他学术-行业合作伙伴能够将[68 Ga]DOTATOC PET/CT图像引导[90 Y]DOTATOC治疗带到美国，用于NET患者。 公共卫生相关性：与目前可用的任何治疗相比，图像引导的分子靶向肽受体放射治疗（PRRT）在神经内分泌肿瘤（NET）患者中提供了上级应答率;然而，它不适用于神经内分泌肿瘤（NET）患者。 美国的我们的提案旨在通过开发[68 Ga]DOTATOC PET/CT和使用[90 Y]DOTATOC进行剂量测定指导的PRRT的标准化方法来纠正这种情况。为初始临床试验生成的IND将通过核医学临床试验网络协会免费提供，导致我们的行业合作伙伴Eckert-Zeigler和Molecular Insight Pharmaceuticals提交新药申请（NDA）。最终结果将是使[68 Ga]DOTATOC PET/CT和[90 Y]DOTATOC PRRT在美国广泛用于NET患者。

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. PUBLIC HEALTH RELEVANCE: 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 and Molecular Insight Pharmaceuticals. The end result will be to make [68Ga]DOTATOC PET/CT and [90Y]DOTATOC PRRT widely available in the US for patients with NETs.