ProstaFluor FDA Trial for Real-Time Margin Detection During Prostatectomy

描述（由申请人提供）：在FDA批准的5年学术-工业合作中，经验丰富的团队和合作伙伴（包括Cornell、范德比尔特、Intuitive Surgical、LI COR和Sand Hill Institute）将通过FDA批准将前列腺靶向荧光造影剂用于人体，该造影剂在之前的R44项目中得到证明，可真实的实时检测动物体内的残留肿瘤。未满足的需求是，由于手术切缘处的前列腺肿瘤在真实的时间内无法检测到，所以在所有前列腺切除术中，30%的患者发生切缘处的残留肿瘤。这类患者局部复发、转移和死亡的风险显著较高，并且还需要放射治疗。相比之下，即使是肿瘤向前列腺外扩展的患者，如果在手术过程中清除肿瘤边缘，效果也会更好。我们建议利用我们的经验和我们的动物证明剂合成，获得FDA IND批准，并在96名人类受试者中进行I/II期试验。我们的试剂由商业LICOR荧光染料和来自Cornell和Millennium Pharmaceuticals的人源化抗体（huJ-591）制成。靶向抗体标记所有管腔来源的前列腺细胞，并且在先前的资助中证明，在动物中前列腺细胞与附近组织相比产生4-12倍的对比度。该设备将使用Intuitive Surgical的荧光敏感手术系统进行现场测试，Intuitive Surgical是一家价值100亿美元的机器人手术公司。该资助的主要研究者之前已经开发并商业化了基础光学技术，他（1）在斯坦福大学共同开发了第一个体内荧光素酶成像系统，并共同创立了Xenogen，以及（2）他开发了T-Stat（R），这是FDA批准的第一个用于组织血流不足的检测系统。其他团队成员合成了用于商业用途的染料缀合物，并通过FDA批准管理基于抗体的药物制剂。公司合作伙伴LiCor（使用近红外设备和染料的自动测序仪器和试剂的世界领导者）和Sand Hill Institute（在抗体配制方面经验丰富）以及Intuitive Surgical提供了造影剂和FDA批准的成熟商业转化经验。这些小组将制定和合成代理，导致FDA IND备案和人体临床试验。替代路径在每个阶段最大限度地减少风险。如果成功，这种商业染料将与一家主要手术工具合作伙伴一起准备进行III期多中心试验，这是一条昂贵且必需的市场引入途径。主要的成像公司（西门子、菲利普斯、通用电气等）也有分子成像项目，该合同代理将适合这些项目。一种成功的显像剂可能会被采用。设想使用叶状II型受体和其他靶点扩展到卵巢癌，包括与其他组开发的其他靶向抗体一起使用。我们预计，这将是人类受试者中许多实时手术靶向光学造影剂中的第一种。直接应用的领域是前列腺癌术中淋巴扩散的检测，以及使用叶酸的卵巢癌。 我们预计，这种设备在癌症中的市场可能合理地在数亿美元/年。 SF-424表格摘要 公共卫生相关性：前列腺癌是男性中最常见的癌症，影响的男性与被诊断患有乳腺癌的女性一样多，每年杀死的男性与乳腺癌杀死的女性一样多。最常见的手术治疗是前列腺切除术，即切除前列腺。在前列腺手术中，肿瘤保留在手术边缘，称为残留肿瘤，占所有前列腺切除术的30%。这样的患者具有显著更高的癌症局部复发风险和更高的死亡率。相比之下，即使是前列腺以外但仍在前列腺附近的癌症患者，在手术过程中清除肿瘤边缘时也会做得更好。我们建议减少手术后残留肿瘤的患者数量。我们将在病人身上测试一种荧光分子，这种分子可以在手术中检测到癌症。如果这项试验按设计进行，我们将减少必须接受额外治疗的患者数量，例如对下腹部进行高剂量放射治疗，因为残留肿瘤的数量已经减少到最低限度。这也可能导致更高的生存率。我们采用的这种癌症检测类型称为分子成像。我们相信，分子影像学将是改善诊断、个体化治疗选择和治疗监测的关键。如果成功，将在本研究后与公司成像合作伙伴进行大型人体试验。

DESCRIPTION (provided by applicant): In this 5 year academic-industrial partnership to FDA approval, an experienced team and partners including Cornell, Vanderbilt, Intuitive Surgical, LI COR, and Sand Hill Institute, will move a prostate-targeted fluorescent contrast agent, demonstrated in a prior R44 project to allow real time detection of residual tumor in animals, through FDA approval to human use. The unmet need is that because prostate tumor at the surgical margin is undetectable in real time, residual tumor at the margin occurs in 30% of all prostatectomies. Such patients have a significantly higher risk of local recurrence, metastasis, and death, and also require radiation therapy. In contrast, even patients with extra prostatic extension of tumors do better when the margins are made clean of tumor during surgery. We propose to leverage our experience and our animal proven agent to synthesize, receive FDA IND approval on, and Phase I/II test our targeted fluorescent conjugate in a pilot study in 96 human subjects. Our agent is made from a commercial LICOR fluorescent dye, and a humanized antibody from Cornell and Millennium Pharmaceuticals (huJ-591). The targeted antibody tags all prostate cells of luminal origin, and was demonstrated in prior funding to produce 4-12 fold contrast for prostate cells over nearby tissues in animals. The device will be tested a sites using a fluorescence-sensitive surgery system from Intuitive Surgical, a $10 billion robotic surgery company. The PI of this grant has previously developed and commercialized fundamental optical technologies he (1) co-developed the first in vivo luciferase imaging system at Stanford and co-founded Xenogen, and (2) he developed T- Stat(R), the first FDA approved detection system for insufficient blood flow to tissue. Other team members have synthesized dye conjugates for commercial use, and managed antibody based drug formulation through FDA approval. The corporate partners, LiCor (a world leader in automated sequencing instruments and reagents using near infrared devices and dyes) and Sand Hill Institute (experienced at antibody formulation), and Intuitive Surgical, provide proven commercial translational experience in contrast agents and FDA approval. These groups will formulate and synthesize the agent, leading to FDA IND filing and human clinical testing. Alternative paths minimize risks at each stage. If successful, the commercial dye will be readied for Phase III multi-center trial with a major surgical tool partner, a costly and required path to market introduction. Major imaging companies (Siemens, Phillips, GE, and others) also have molecular imaging programs, into which this contract agent will fit. A successful imaging agent would likely be adopted. Extensions to ovarian cancer using the foliate type II receptor, and other targets, are envisioned, including use with other targeting antibodies developed by other groups. We anticipate that this will be among the first of many real-time surgery-targeting optical contrast agents in human subjects. Areas with immediate application are the detection of lymphatic spread intraoperatively for prostate cancer, as well as for ovarian cancer using a Folate. We expect that the market for such a device in cancer could reasonably be in the hundreds of millions of dollars/year. Form SF-424 Abstract PUBLIC HEALTH RELEVANCE: Prostate Cancer is the most common cancer in men, affecting about as many men as women diagnosed with breast cancer, and killing about as many men per year as breast cancer kills women. The most common surgical treatment is prostatectomy, the removal of the prostate. During prostate surgery, tumor remains at the edge of the surgery, called residual tumor, in 30% of all prostatectomies. Such patients have a significantly higher risk of local recurrence of the cancer, and higher rates of death. In contrast, even patients with cancer outside of the prostate, but still nearby the prostate, do better when the margins are made clean of tumor during surgery. We propose to reduce the number of patients with residual tumor after surgery. We will test in patients a fluorescent molecule that allows cancer to be detected during surgery. If this trial works as designed, we will reduce the number of patients who have to receive additional treatment, such as high doses of radiation to the lower abdomen, because the amount of residual tumor left behind has been minimized. This may also lead to higher rates of survival. This type of detection of cancer we employ is called Molecular imaging. We believe that molecular imaging will be the key to improved diagnosis, individualized treatment selection, and treatment monitoring. If successful, a large human trial will be conducted after this study with a corporate imaging partner.