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

描述(申请人提供)：在标准治疗失败后，SRC/Abl肿瘤激酶抑制已被临床证明对常见的固体癌症类型有效，使一小部分患者--可能是全球数百万人--受益。随着一波新的Src/Abl疗法的发展，肿瘤学家迫切需要新的以Src/Abl为靶点的检测方法，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治疗的反应。如果找不到合适的检测方法，可能会因为总体应答率低而放弃Src/Abl实体瘤治疗，而对可能对Src/Abl靶向治疗有反应的数百万进展性实体癌患者来说，将失去好处。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，可以评估以Src/Abl为靶点的小分子靶向患者体内肿瘤的情况。研究人员预测，通过医学成像检测Src/Abl肿瘤靶向，将预测哪些患者将受益于Src/Abl靶向治疗，并为规划如何开出Src/Abl治疗提供新的见解。研究人员开发了18F-SKI-249380，这是第一种达沙替尼示踪剂，作为正电子发射断层扫描的Src/Abl靶向显像剂。研究人员需要了解以Src/Abl为靶标的示踪剂在人体内的行为，以及它提供的辐射剂量，这是合理设计18F-SKI-249380正电子发射计算机断层扫描临床试验成功的先决条件。解决方案：使用微克示踪剂量的18F-SKI-249380，在患者毒性风险最小的情况下进行人类首个试点试验，进行正电子发射计算机断层扫描和血液分析，以获得关于剂量学、新陈代谢、生物分布和排泄的首个人类数据。所寻求的资金用于支付计划中的第一次人体试验的直接成本。研究人员是一支积极进取的团队，在成功的临床开发达沙替尼示踪剂PET成像方面具有卓越的资质：18F-SKI-249380的发明者；纪念斯隆-凯特琳癌症中心PET/核医学服务、放射化学-回旋加速器核心、医学物理系和肿瘤学服务的经验丰富的主治医师，包括达沙替尼和其他Src/Abl疗法的MSKCC实体肿瘤试验的主要和联合研究员。该团队的集体经验和长期合作为肿瘤成像新的PET示踪剂的翻译开发提供了成功的记录。 与公共健康相关：新的抗癌药物，即Src/Abl抑制剂，即使在标准治疗失败后，也能让肺癌、乳腺癌和前列腺癌等常见实体癌症患者中的一小部分人受益；受益率可能意味着帮助全球数百万人。没有可用的临床试验可以预测谁将受益，或者如何最好地开出Src/Abl抑制剂，这严重阻碍了正在进行的早期实体肿瘤治疗试验。为了解决这一未得到满足的临床需求，研究人员正在进行无创正电子发射断层扫描(PET)成像研究的首次人体试验，该研究评估了Src/Abl抑制剂针对患者体内肿瘤的效果，这将为肿瘤学家在Src/Abl靶向治疗的患者选择和剂量策略方面提供迫切需要的指导。

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.