QBS10072S for the Treatment of Brain Metastatic Triple-Negative Breast Cancer

项目总结 Quadriga Biosciences的新小分子疗法QBS-72S将DNA烷化部分与 一种利用L氨基酸转运蛋白1实现跨膜转运的氨基酸类似物 血脑屏障(BBB)和肿瘤细胞的选择性蓄积。临床前研究的结果表明 QBS-72可能对多种癌症类型引起的脑转移(脑转移瘤)有效，包括 三阴性乳腺癌(TNBC)目前，对TNBC患者脑组织甲硫氨酸的治疗仅限于 手术干预或放射治疗，药物开发由于挑战 通过BBB运送有效的药剂。在这份直接到第二阶段的SBIR中，Quadriga提议进行 2a期概念验证临床试验在TNBC导致的脑MET患者中进行，以测试安全性和 采用西蒙两阶段设计的QBS-72的疗效。这项研究的数据预计将为设计 一项关键的第三阶段试验。瞄准。QBS-72S治疗颅脑损伤患者的安全性和有效性评价 转移瘤。斯坦福大学的医生将确认多达25名患有TNBC和Brain Mets的患者 及其基于大脑对比磁共振成像的转诊网络。参赛者将得到最高待遇 QBS-72的耐受量(MTD)每4周静脉注射一次，最长持续2年。肿瘤生长 将在每次用药的前一天和每隔一个月用核磁共振进行评估 之后。主要终点是客观应答率(即≤增长25%的患者的百分比 在肿瘤大小方面，3个月后肿瘤大小没有变化，或肿瘤大小缩小)。次要终端包括 总生存期、无进展生存期、全身性疾病反应、不良事件和变化 在实验室评估的患者参数中。里程碑：使用Simon的两阶段Minimax设计，如果有两个或更多 用QBS-72治疗的前15名可评估的TNBC患者实现了客观的肿瘤反应 ，这项研究将 再招收10名患者。如果有6名或更多的患者(总共25名)在3个月内有客观的肿瘤反应 在开始治疗的几个月后，我们将与FDA会面，讨论患者注册试验的设计 以及由TNBC产生的Brain Mets。影响-成功完成这些研究将确立 为随后的3期临床试验奠定基础。QBS-72s是否能有效治疗脑部甲状旁腺素 有了TNBC，它将成为第一个专门针对这一人群的化疗药物。调查结果： 疗效也将支持进一步探索使用QBS-72治疗其他脑转移瘤患者 癌症，包括肺癌和黑色素瘤。此外，由于LAT1在许多其他形式上高度表达 对于侵袭性癌症，QBS-72可能适用于治疗全身癌症和中枢神经系统转移癌， 尤其是在像TNBC这样的疾病中，治疗选择很少。

PROJECT SUMMARY Quadriga Biosciences’ new small molecule therapeutic, QBS-72S, combines a DNA alkylating moiety with an amino acid analogue that leverages the L-Type Amino Acid Transporter 1 (LAT1) to achieve transport across the blood brain barrier (BBB) and selective accumulation in tumor cells. Results from preclinical studies suggest QBS-72S is likely effective against brain metastases (brain mets) resulting from multiple cancer types, including triple negative breast cancer (TNBC). Currently, treatment for brain mets in patients with TNBC is limited to surgical intervention or radiotherapy, and drug development has been unsuccessful due to the challenge of transporting effective agents across the BBB. In this Direct-to-Phase II SBIR, Quadriga proposes to conduct a Phase 2a proof-of-concept clinical trial in patients with brain mets resulting from TNBC to test the safety and efficacy of QBS-72S using a Simon’s two-stage design. Data from this study is expected to inform the design of a pivotal Phase 3 trial. Aim. Evaluate the safety and efficacy of QBS-72S in TBNC patients with brain metastases. Up to 25 patients with TNBC and brain mets will be identified by physicians at Stanford University and its referral network based on contrast MRI of the brain. Participants will be treated with the maximum tolerated dose (MTD) of QBS-72S administered intravenously every four weeks for up to 2 years. Tumor growth will be assessed by MRI the day prior to each administration for the first four months and every other month thereafter. The primary endpoint is objective response rate (i.e., the percentage of patients with ≤ 25% growth in tumor size, no change in tumor size, or reduction in tumor size) at 3 months. Secondary endpoints include overall survival, length of progression-free survival, response of systemic disease, adverse events, and changes in lab-assessed patient parameters. Milestones: Using a Simon's two-stage Minimax design, if two or more of the first 15 evaluable TNBC patients treated with QBS-72S achieve an objective tumor response , the study will enroll 10 additional patients. If six or more patients (out of 25 total) have an objective tumor response within 3 months after initiating therapy, we will meet with the FDA to discuss the design of a registration trial for patients with brain mets resulting from TNBC. Impact—Successful completion of these studies will establish the foundation for a subsequent Phase 3 clinical trial. If QBS-72S proves efficacious in treating brain mets in patients with TNBC, it would be the first chemotherapeutic agent available specifically for this population. Findings of efficacy would also support further exploration into using QBS-72S to treat patients with other brain metastatic cancers, including lung cancer and melanoma. In addition, since LAT1 is highly expressed on many other forms of aggressive cancer, QBS-72S may be suitable for treating both systemic cancers and CNS metastases, especially in diseases like TNBC where there are few therapeutic options.