ProstaFluor FDA Trial for Real-Time Margin Detection During Prostatectomy

描述(由申请人提供)：在FDA批准的这项为期5年的学术和产业合作伙伴关系中，经验丰富的团队和合作伙伴包括康奈尔大学、Vanderbilt公司、Intuitive Surgical公司、Li COR公司和沙山研究所，将通过FDA的批准将一种前列腺靶向荧光造影剂转移到人类使用，该造影剂在先前的R44项目中得到了演示，可以实时检测动物体内的肿瘤残留。尚未满足的需求是，由于手术边缘的前列腺癌无法实时检测，所有前列腺切除术中30%的边缘会出现残留肿瘤。这类患者的局部复发、转移和死亡的风险要高得多，而且还需要放射治疗。相比之下，即使是有额外的前列腺癌延伸的患者，在手术中清除肿瘤的边缘时也会做得更好。我们建议利用我们的经验和我们的动物验证试剂来合成我们的靶向荧光结合物，并获得FDA IND的批准，并在96名人类受试者中进行I/II期测试。我们的试剂是由商业许可证荧光染料和来自康奈尔和千禧制药公司(HuJ-591)的人源化抗体制成的。这种靶向抗体标记了所有腔内起源的前列腺细胞，并在之前的研究中证明，在动物体内，前列腺细胞的对比度是附近组织的4-12倍。该设备将使用直觉外科公司的荧光敏感手术系统在多个地点进行测试，直觉外科公司是一家市值100亿美元的机器人手术公司。这笔赠款的私人助理此前曾开发基本光学技术并将其商业化。他(1)在斯坦福大学共同开发了第一个活体荧光素酶成像系统，并与人共同创立了Xenogen，以及(2)他开发了T-Stat(R)，这是FDA批准的第一个组织血流不足检测系统。其他团队成员已经合成了用于商业用途的染料结合物，并通过FDA批准管理基于抗体的药物配方。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领域的世界领先企业)和沙山研究所(在抗体配方方面经验丰富)和直觉外科公司在造影剂和FDA批准方面提供经过验证的商业翻译经验。这些小组将配方和合成该试剂，导致FDA IND申请和人体临床测试。替代路径将每个阶段的风险降至最低。如果成功，这种商业染料将准备好与主要手术工具合作伙伴进行第三阶段多中心试验，这是一条昂贵且必需的市场推介途径。主要的成像公司(西门子、菲利普斯、通用电气和其他公司)也有分子成像项目，该合同代理将适合这些项目。一种成功的显像剂很可能会被采用。利用叶酸II型受体和其他靶点，包括与其他小组开发的其他靶向抗体一起使用，可以扩展到卵巢癌。我们预计，这将是许多实时手术靶向光学造影剂在人类受试者中的首批产品之一。立即应用的领域是前列腺癌手术中淋巴扩散的检测，以及使用叶酸的卵巢癌。我们预计，这种治疗癌症的设备的市场可能合理地达到每年数亿美元。表格SF-424摘要 公共卫生相关性：前列腺癌是男性中最常见的癌症，影响被诊断为乳腺癌的男性和女性的人数差不多，每年导致男性死亡的人数和乳腺癌导致女性死亡的人数一样多。最常见的外科治疗是前列腺切除术，即摘除前列腺。在前列腺手术中，30%的前列腺切除手术中，肿瘤残留在手术的边缘，称为残留肿瘤。这类患者的癌症局部复发风险和死亡率都明显较高。相比之下，即使是前列腺癌以外但仍在前列腺癌附近的患者，在手术期间清除肿瘤边缘时，情况也会更好。我们建议减少术后残留肿瘤的患者数量。我们将在患者身上测试一种荧光分子，这种分子可以在手术过程中检测到癌症。如果这项试验如设计的那样奏效，我们将减少必须接受额外治疗的患者数量，例如下腹部的高剂量放射，因为遗留下来的肿瘤残余量已经降至最低。这也可能导致更高的存活率。我们使用的这种癌症检测方法被称为分子成像。我们相信，分子成像将是改善诊断、个体化治疗选择和治疗监测的关键。如果成功，在这项研究之后，将与一家公司成像合作伙伴一起进行一项大型人体试验。

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.