Advancing molecular fluorescence-guided surgery platform

先进的分子荧光引导手术平台

• 批准号: 10598545
• 负责人: KEITH D. PAULSEN
• 金额: $ 54.79万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598545
• 关键词: Acceleration; Adverse effects; Aminolevulinic Acid; Animal Model; Biological Sciences; Clinical; Clinical Research; Custom; Data; Detection; Development; Diagnostic; Disease; Dose; EGFR Protein Overexpression; Engineering; Epidermal Growth Factor Receptor; Excision; Fluorescence; Fluorescent Dyes; Funding; Glioma; Goals; Good Manufacturing Process; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Image; Imaging technology; In Situ; Industrialization; Infiltration; Infrastructure; Intellectual Property; Investigational Drugs; Investigational New Drug Application; Left; Limb structure; Malignant Neoplasms; Methodology; Microscope; Molecular; Molecular Target; Names; New Drug Approvals; No-Observed-Adverse-Effect Level; Oncology; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Performance; Pharmaceutical Preparations; Phase; Phase 0 Clinical Trial; Phase 0 Trial; Phase II Clinical Trials; Probability; Procedures; Productivity; Protocols documentation; Randomized; Research Personnel; Resectable; Residual state; Risk; Safety; Secondary to; Sensitivity and Specificity; Signal Transduction; Soft tissue sarcoma; Solid Neoplasm; Structure; Surgical Oncology; Surgical margins; System; Testing; Tissue imaging; Tissues; Toxic effect; Toxicity Tests; Tracer; Translating; Translations; Tumor Tissue; Work; bench to bedside; carboxylate; carboxylation; clinical development; clinical translation; cost; cost effective; design; detection sensitivity; drug development; efficacy study; efficacy testing; experience; first-in-human; fluorescence-guided surgery; fluorophore; imaging agent; imaging capabilities; imaging system; improved; in vivo; industry partner; instrumentation; medical schools; minimally invasive; neurosurgery; novel; phase 2 designs; phase 2 study; phase 2 testing; phase 3 study; phase II trial; pre-clinical; preclinical toxicity; primary endpoint; research clinical testing; standard of care; success; surgery outcome; synthetic peptide; timeline; tumor

ABSTRACT This Academic-Industrial Partnership (AIP) will further the clinical development of fluorescence guided surgery (FGS) through the utilization of the FDA exploratory Investigational New Drug (eIND) pathway. While recent advances in both imaging agents and technology for FGS has been impressive, significant limitations remain in detecting low dose administration of imaging agents and obtaining true molecular contrast between the tumor and normal surrounding tissues. The basis of this application and the underlying tenet of the proposed AIP is that a cost-effective, risk-diluted approach to clinical translation of imaging methodologies is needed in order to realize the promise of FGS. Utilization of our previously developed bench-to-clinic pipeline stands to accelerate surgical oncology to revolutionize both the procedures that are possible and the surgical outcomes that will result. In the first funding cycle our AIP implemented a low-cost testing pipeline for ABY-029, a fluorescent epidermal growth factor receptor-targeted synthetic peptide. We established the necessary protocols to bring ABY-029 from pre-clinical animal models into three Phase 0 clinical trials using the FDA eIND pathway (eIND #122681). We will build upon our previous success to apply for Investigational New Drug (IND) status of ABY-029 for economical, investigator-led Phase II testing of detection accuracy in glioma and head and neck cancers. Sim- ultaneously, we will utilize the pipeline to achieve eIND approval of paired-agent imaging. The proposed AIP between Dartmouth (Engineering and Medical Schools), Affibody AB, LI-COR, and DoseOptics brings together 4 partners who have the intellectual property (IP), expertise and infrastructure to develop, test and advance molecular-targeted fluorescent tracers and imaging systems for surgical guidance. Clinical translation and testing of FGS will be achieved through the completion of the following aims: Aim 1 - Advance near-microdose ABY-029 FGS for resection of primary high-grade glioma in a Phase 2 trial; Aim 2 - Adapt FGS system for minimally invasive resection of head and neck cancers for Phase 2 testing; and Aim 3 - Leverage the Dartmouth fluorescent agent development pipeline to bring quantitative molecular paired- agent imaging (PAI) to Phase 0 trial using a cocktail of ABY-029 and IRDye 680LT carboxylate (pABY-IR680). The translational INNOVATION will include advancement of ABY-029 into Phase II clinical trials, first-in-human implementation of paired-agent imaging for true molecular contrast via the established bench-to-clinic eIND pipe- line, and the integration of a highly sensitive, multi-channel near infrared surgical camera imaging system capa- ble of imaging in full surgical lights. The SIGNIFICANCE of this AIP will be to demonstrate improved margin detection for surgical resection of glioma and head and neck cancers using a low-cost, efficient testing pipeline.

摘要 该学术-工业合作伙伴关系（AIP）将进一步促进荧光引导手术的临床发展 (FGS)通过使用FDA探索性研究新药（eIND）途径。虽然最近 FGS的成像剂和技术的进步令人印象深刻，但在成像方面仍存在显著的局限性。 检测成像剂的低剂量施用并获得肿瘤之间的真实分子对比， 和周围正常组织。本申请的基础和拟议AIP的基本原则是 需要一种具有成本效益的、风险稀释的方法来对成像方法进行临床转化， 实现FGS的承诺。利用我们以前开发的从工作台到诊所的管道支架， 外科肿瘤学，以彻底改变可能的程序和手术结果。 在第一个融资周期中，我们的AIP实施了ABY-029的低成本测试管道， 生长因子受体靶向合成肽。我们建立了必要的协议 使用FDA eIND途径（eIND #122681），将临床前动物模型转化为三项0期临床试验。 我们将在先前成功的基础上，申请ABY-029的研究性新药（IND）地位， 这是一个经济的、由肿瘤检测仪主导的神经胶质瘤和头颈癌检测准确性的II期试验。西姆- 最后，我们将利用管道实现配对药物成像的eIND批准。拟议的AIP 达特茅斯（工程和医学院），Affibody AB，LI-COR和DoseOptics之间的合作 4个拥有知识产权（IP）、专业知识和基础设施的合作伙伴，可用于开发、测试和推进 分子靶向荧光示踪剂和用于手术指导的成像系统。 FGS的临床翻译和测试将通过完成以下目标来实现： 目的1 -在2期试验中推进近微剂量ABY-029 FGS用于切除原发性高级别胶质瘤; 目标2 -调整FGS系统用于头颈部癌症的微创切除术，以进行第2阶段测试;以及 目标3 -利用达特茅斯荧光剂开发管道， 图1显示了使用ABY-029和IRDye 680 LT羧酸盐（pABY-IR 680）的混合物的0期试验的药物显像（派）的结果。 翻译创新将包括推进ABY-029进入II期临床试验，首次在人体内 通过已建立的从实验室到临床的eIND管道，实现真正分子对比的配对试剂成像- 线，并集成了高灵敏度，多通道近红外手术摄像成像系统capa- 在全手术光下成像的能力。该AIP的意义在于证明边缘改善 使用低成本、高效的检测管道检测神经胶质瘤和头颈癌的手术切除。