Improving lung cancer surgery with an intraoperative, tumor-targeted, activatable fluorescent imaging agent

项目总结/摘要 美国今年将有超过228，000人被诊断为肺癌。只有14%-49%的 早期患者在诊断后至少存活5年， 晚期IIIB或IV期患者。肿瘤切除后复发是影响这些的关键因素， 可怜的小家伙们。如果在手术过程中留下任何癌组织， 复发率急剧增加。这些复发性肿瘤迅速扩散并对患者的健康产生负面影响。 临床展望因此，在手术切除过程中准确识别肿瘤组织至关重要。尽管如此 需要，将术前图像转换到手术室进行实时，精确的可视化仍然是一个 挑战;在肺癌的术中环境中，组织经常移位，肺放气， 血液会模糊手术视野Vergent Bioscience，Inc.开发了一种分子成像剂VGT-309， 以满足对改进肿瘤的术中可视化的迫切需要。该药剂作为 在手术前单次静脉内给药，之后它将与癌组织中上调的组织蛋白酶结合。 组织被激活并发出荧光然后，可商购的近红外（NIR）成像系统可以 在手术过程中用于照亮肿瘤，使外科医生能够精确识别和切除肿瘤 边缘，确保没有留下癌组织。VGT-309具有较宽的剂量后成像窗口， 无缝集成到现有的手术工作流程中，无需额外的培训或设备。 广泛的临床前安全性、有效性和剂量研究已经验证了VGT-309的使用，以促进 切除各种类型的实体瘤。一项I期随机、双盲、安慰剂对照、单次给药 在健康受试者中进行的剂量递增研究于2021年初完成，以评估安全性、耐受性和 VGT-309的药代动力学。在本试验期间，所有四种剂量均安全且耐受性良好，因此起始剂量为 对于目前入组正在进行的II期临床试验的肺癌患者，选择0.05 mg/kg 在澳大利亚进行的一项试验，以确定最佳的VGT-309剂量和时间。在目前的直接到第二阶段 申请后，Vergent将1）按照当前药品生产质量管理规范生产VGT-309制剂 实践，2）与宾夕法尼亚大学医院合作，在一个 II期、开放标签研究，旨在评估其在35例计划接受 疑似或确诊肺癌的标准护理手术切除。一旦在我们的 II期临床试验VGT-309将在更大的多中心2b期和III期研究中进行评价。最后， 我们计划将这种荧光、可激活的分子成像剂的应用扩展到其他实体瘤， 如结肠直肠、头颈部、卵巢、脑、胃和乳腺。这种药物有可能改变 手术肿瘤学空间和优化的临床结果进行肿瘤切除的患者。

PROJECT SUMMARY/ABSTRACT More than 228,000 people in the United States will receive a lung cancer diagnosis this year. Only 14%-49% of early-stage patients survive at least 5 years after their diagnosis, and the survival rates fall below 5% for patients with advanced-stage IIIB or IV. Tumor recurrence after resection is a critical factor influencing these poor prognoses. If any cancerous tissue is left behind during surgery, the risk of an aggressive tumor recurrence increases dramatically. These recurrent tumors rapidly spread and negatively impact a patient’s clinical outlook. Therefore, accurately identifying tumor tissue during surgical resection is crucial. Despite this need, translating preoperative images into the surgical suite for real-time, precise visualization remains a challenge; in an intraoperative setting for lung cancer, tissues are often displaced, lungs are deflated, and blood can obscure the surgical field. Vergent Bioscience, Inc. developed a molecular imaging agent, VGT-309, to meet this urgent need for improved intraoperative visualization of tumors. This agent is administered as a single intravenous dose prior to surgery, after which it will bind to upregulated cathepsins in the cancerous tissue, become activated, and fluoresce. Commercially available near-infrared (NIR) imaging systems can then be used during surgery to illuminate the tumor and enable surgeons to precisely identify and remove tumor margins, ensuring no cancerous tissue is left behind. VGT-309 has a wide post-dose imaging window and can be seamlessly integrated into existing surgical workflows without requiring additional training or equipment. Extensive preclinical safety, efficacy, and dosing studies have validated the use of VGT-309 to facilitate the resection of a variety of solid tumor types. A Phase 1 randomized, double-blind, placebo-controlled, single ascending dose study in healthy subjects was completed in early 2021 to evaluate the safety, tolerability, and pharmacokinetics of VGT-309. All four doses were safe and well-tolerated during this trial, so a starting dose of 0.05mg/kg was selected for patients with lung cancer who are currently enrolled in an ongoing Phase 2 clinical trial in Australia to determine optimal VGT-309 dose and timing. During the present Direct to Phase II application, Vergent will 1) manufacture VGT-309 drug product following Current Good Manufacturing Practices, and 2) collaborate with the Hospital of the University of Pennsylvania to evaluate this agent in a Phase 2, open-label study to assess its safety, tolerability, and efficacy in 35 patients scheduled to undergo standard of care surgical resection for suspected or proven lung cancer. Once successfully validated in our Phase 2 clinical trial, VGT-309 will be evaluated in larger, multi-site Phase 2b and Phase 3 studies. Ultimately, we plan to expand the use of this fluorescent, activatable molecular imaging agent to other solid tumors such as colorectal, head and neck, ovarian, brain, gastric, and breast. This agent has the potential to transform the surgical oncology space and optimize clinical outcomes for patients undergoing resection of tumors.