First Human Trial of Src/Abl-Targeted PET Tumor Imaging with F-18 SKI-249380

描述（由申请人提供）：Src/Abl肿瘤激酶抑制剂对标准治疗失败后的常见实体类型癌症具有临床证明的疗效，使一个亚组的患者受益-全球可能有数百万人受益。随着一波新的Src/Abl疗法的开发，肿瘤学家迫切需要新的Src/Abl靶向测定，可以告诉他们哪些患者将受益;指导给药策略;并帮助他们在分子水平上了解肿瘤对Src/Abl疗法的反应。如果没有发现合适的测定，Src/Abl实体瘤治疗可能会因为低的总体响应率而被放弃，并且潜在的数百万患有进展性实体癌的患者将失去对Src/Abl靶向治疗有响应的益处。研究人员提出了一种新的Src/Abl诊断方法：一种非侵入性扫描，可以评估Src/Abl靶向小分子靶向患者体内肿瘤的程度。研究人员预测，通过医学成像检测Src/Abl肿瘤靶向，将预测哪些患者将从Src/Abl靶向治疗中获益，并为计划如何处方Src/Abl治疗提供新的见解。研究人员开发了18F-SKI-249380，这是首个达沙替尼示踪剂，作为正电子发射断层扫描（PET）的Src/Src靶向成像剂。研究者需要了解Src/Src靶向示踪剂在人体中的行为以及它提供的辐射剂量，这是合理设计18F-SKI-249380 PET临床试验成功的先决条件。解决方法：一项首次人体初步试验，使用微克示踪剂剂量的18F-SKI-249380，患者毒性风险最小，PET成像和血液测定，以获得剂量测定、代谢、生物分布和排泄的首次人体数据。所寻求的资金包括计划进行的首次人体试验的直接费用。研究者是一个积极的团队，具有成功临床开发达沙替尼示踪剂PET成像的杰出资格：18F-SKI-249380的发明者; Memorial Sloan Kettering Cancer Center（MSKCC）PET/核医学服务、放射化学-回旋加速器核心、医学物理部门和肿瘤服务的经验丰富的主治人员，包括MSKCC实体瘤试验的主要研究者和合作研究者，使用达沙替尼和其他Src/Abl疗法。该团队的集体经验和长期合作为肿瘤成像新PET示踪剂的转化开发提供了成功的记录。 公共卫生相关性：新的抗癌药物Src/Abl抑制剂，即使在标准治疗失败后，也能使一部分患有常见实体癌（如肺癌、乳腺癌和前列腺癌）的患者受益;其受益率可能意味着对全世界数百万人的帮助。没有可用的临床试验可以预测谁将受益或如何Src/Abl抑制剂可以最好地处方，严重阻碍了正在进行的早期实体瘤治疗试验。为了解决这一未满足的临床需求，研究人员正在进行第一项非侵入性正电子发射断层扫描（PET）成像研究的人体试验，该研究评估Src/Abl抑制剂靶向患者体内肿瘤的效果，这将为肿瘤学家提供Src/Abl靶向治疗中患者选择和给药策略方面急需的指导。

DESCRIPTION (provided by applicant): Src/Abl tumor kinase inhibition has clinically-proven efficacy against common solid types of cancer after standard therapy has failed, benefitting a subgroup of patients - potentially millions of people worldwide. With a wave of new Src/Abl therapeutics in development, oncologists urgently need new Src/Abl -targeted assays that can tell them which patients will benefit; guide dosing strategy; and help them understand tumor response to Src/Abl therapy at the molecular level. If no suitable assays are found, Src/Abl solid tumor therapy may be abandoned for low overall response-rates, and the benefits to potentially millions of patients with progressive solid cancer who would have responded to Src/Abl -targeted therapy will be lost. The Investigators propose a new approach to Src/Abl diagnostics: a non-invasive scan that can evaluate how well a Src/Abl-targeted small molecule targets tumors inside patients. The Investigators predict that detection of Src/Abl tumor-targeting, through medical imaging, will predict which patients will benefit from Src/Abl-targeted therapy and provide new insights for planning how to prescribe Src/Abl-therapy. The Investigators have developed 18F-SKI-249380, a first-of-its-kind dasatinib-tracer, as a Src/Abl-targeted imaging agent for positron emission tomography (PET) scanning. The Investigators need to learn how the Src/Abl-targeted tracer behaves in humans, and the radiation dose it delivers, as a prerequisite to rational design of successful clinical trials with 18F-SKI-249380 PET. Solution: A first-in-human pilot trial, using microgram tracer-dose of 18F-SKI-249380, with minimal risk of patient toxicity, PET imaging and blood assays to obtain first-in-human data on dosimetry, metabolism, biodistribution, and excretion. The funding sought covers direct costs of the planned first in-human trial. The Investigators are a motivated team with distinguished qualifications for successful clinical development of dasatinib-tracer PET imaging: the inventor of 18F-SKI-249380; experienced attending staff in the Memorial Sloan Kettering Cancer Center (MSKCC) PET/Nuclear Medicine Service, Radiochemistry- Cyclotron Core, Medical Physics Department, and Oncology Services, including principal & co-investigators of MSKCC solid tumor trials with dasatinib and other Src/Abl therapeutics. The team's collective experience and longstanding collaborations offer a track-record of success in translational development of new PET tracers for oncologic imaging. PUBLIC HEALTH RELEVANCE: New cancer-fighting drugs, Src/Abl inhibitors, benefit a select subgroup of patients with common solid cancers, like lung, breast and prostate cancer, even after standard treatments fail; with a benefit rate that potentially means help to millions of peope worldwide. No available clinical tests can predict who will benefit or how Src/Abl inhibitors can best be prescribed, seriously hindering ongoing early phase solid- tumor therapy trials. To address this unmet clinical need, the Investigators are conducting the first in- human trial of a non-invasive positron emission tomography (PET) imaging study that evaluates how well Src/Abl inhibitors target tumors inside patients, which should provide oncologists urgently needed guidance in patient selection and dosing strategy in Src/Abl-targeted therapy.