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

项目摘要/摘要 今年，美国将有超过22.8万人被诊断患有肺癌。只有14%-49%的 早期患者在确诊后至少存活5年，存活率降至5%以下 晚期IIIB或IV期患者。肿瘤切除后复发是影响这些患者的关键因素 预后不佳。如果在手术过程中留下任何癌组织，发生侵袭性肿瘤的风险 复发率急剧增加。这些复发的肿瘤迅速扩散，并对患者的 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套件中以实现实时、精确的可视化仍然是一项 挑战；在肺癌的术中环境中，组织经常移位，肺排气，以及 血液会遮挡手术的视野。Vergent Bioscience公司开发了一种分子显像剂VGT-309， 以满足这一迫切需要，提高术中肿瘤的可视化。此代理作为 手术前单次静脉注射，之后它将与癌组织中上调的组织蛋白结合 组织，变得活跃，并发出荧光。商业上可用的近红外(NIR)成像系统可以 在手术中用于照亮肿瘤，使外科医生能够准确地识别和切除肿瘤 利润率，确保不会留下任何癌症组织。VGT-309具有较宽的剂量后成像窗口，可以 无缝集成到现有的外科工作流程中，不需要额外的培训或设备。 广泛的临床前安全性、有效性和剂量研究证实了VGT-309的使用有助于 切除多种实体瘤类型。A阶段1随机、双盲、安慰剂对照、单一 2021年初完成了健康受试者的递增剂量研究，以评估其安全性、耐受性和 VGT-309的药代动力学。在这项试验中，所有四种剂量都是安全的，耐受性良好，所以起始剂量 0.05毫克/公斤被选择用于目前正在进行的第二阶段临床试验的肺癌患者 在澳大利亚进行试验，以确定VGT-309的最佳剂量和时机。在目前的直达第二阶段期间 应用，Vergent将1)继目前良好的制造之后生产VGT-309药物产品 实践，以及2)与宾夕法尼亚大学医院合作，在 第二阶段，开放标签研究，评估其安全性、耐受性和有效性，对35名计划接受 疑似或确诊肺癌的外科切除的标准护理。一旦在我们的 VGT-309的2期临床试验将在更大规模的多部位2b期和3期研究中进行评估。最终， 我们计划将这种荧光、可激活的分子显像剂的使用扩大到其他实体肿瘤，如 如结直肠、头颈部、卵巢、脑、胃和乳房。这个代理有可能改变 外科肿瘤学空间，优化肿瘤切除患者的临床结果。

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.