Image-guided Diagnosis and Therapy of Neuroendocrine Tumors

描述(申请人提供)：图像引导、分子靶向的多肽受体放射治疗(PRRT)在神经内分泌肿瘤(NETS)患者中的有效率高于现有的任何治疗方法；然而，它不适用于 美国。我们的建议旨在通过为[68Ga]DOTATOC PET/CT和使用[90Y]DOTATOC的剂量学指导的PRRT开发标准化方法来纠正这种情况。初步临床试验产生的IND将通过核医学会临床试验网络免费提供，导致我们的行业合作伙伴Eckert-Zeigler(EZ)和分子洞察制药(MIP)提交新药申请(NDA)。最终结果将是使[68Ga]DOTATOC PET/CT和[90Y]DOTATOC PRRT在美国广泛用于NETs患者。净发病率在过去30年中增加了5倍，但目前还没有针对大多数此类患者的根治疗法。对于早期确诊的患者，手术是可以治愈的，但80%的患者在确诊时有无法手术的转移，5年生存率为30%，这一事实限制了手术。我们的初步数据显示，美国第一批[68Ga]DOTATOC PET/CT在检测原发和转移病变方面表现出比FDA批准的Octreoscan更高的成像灵敏度和特异度。这些发现有力地支持了我们的建议，即将使用[68Ga]DOTATOC PET/CT的功能和解剖成像结合起来，应用于临床领域，用于诊断、分期和定量测量NETS患者的治疗反应。68Ga在临床上具有优势，因为它可以在不需要回旋加速器的情况下提供PET分辨率；然而，对制造商提供符合监管合规的发电机技术的担忧减缓了FDA在美国的接受程度。我们用GMP DOTATOC(MIP)和镓发生器(EZ)产生的强劲初步数据表明，现在可以使用符合GMP标准的一次性盒式试剂盒(EZ)可靠地制备[68Ga]DOTATOC，从而使临床[68Ga]DOTATOC在美国法规要求的框架内成为可能。没有对照试验检验了使用[68Ga]DOTATOC定量测量治疗反应的可能性，也没有研究将这些努力结合在一项多点前瞻性标准化试验中，这可能会推动这些患者护理方案在美国得到广泛接受。根据PAR-10-169对创新的定义，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方案，使用[68Ga]DOTATOC PET/CT进行诊断、分期和选择最能从[90Y]DOTATOC治疗中受益的患者。这一贡献意义重大，因为它将确定放射性药物配方特征的影响。 关于[68Ga]DOTATOC和[90Y]DOTATOC药物产品的相对有效性，还将产生一个标准化平台，以加快PRRT向多机构临床试验的转换，这将是在美国广泛上市所必需的。据我们所知，没有其他学术-行业合作伙伴能够将[68Ga]DOTATOC PET/CT图像引导的[90年]DOTATOC疗法带到美国，用于治疗NETs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.