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

项目摘要 Quadriga Biosciences的新型小分子治疗剂QBS-72 S将DNA烷基化部分与 一种利用L型氨基酸转运蛋白1（LAT 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积聚。临床前研究结果表明， QBS-72 S可能对多种癌症类型引起的脑转移（脑转移）有效，包括 三阴性乳腺癌（TNBC）。目前，TNBC患者脑转移瘤的治疗仅限于 手术干预或放射治疗，以及药物开发由于以下挑战而不成功： 通过血脑屏障运输有效的药物。在这份直接进入第二阶段的SBIR中，Quadriga建议进行一项 在患有由TNBC引起的脑转移瘤的患者中进行的2a期概念验证临床试验，以测试安全性和 QBS-72 S使用Simon两阶段设计的有效性。本研究的数据预计将为设计提供信息， 一项关键的第三阶段试验瞄准评价QBS-72 S在脑结核性非典型肺炎患者中的安全性和有效性 转移斯坦福大学的医生将确定多达25名TNBC和脑转移瘤患者 以及基于脑部对比MRI的转诊网络。参与者将得到最大限度的 在一个实施方案中，使用QBS-72 S的耐受剂量（MTD）每四周静脉内施用长达2年。肿瘤生长 将在前4个月每次给药前一天和每隔一个月进行MRI评估 然后主要终点是客观缓解率（即，生长≤ 25%的患者百分比 在3个月时，肿瘤大小无变化，或肿瘤大小减小）。次要终点包括 总生存期、无进展生存期长度、全身性疾病缓解、不良事件和变化 实验室评估的患者参数。Military：使用Simon的两阶段Minimax设计，如果两个或两个以上 用QBS-72 S治疗的前15名可评估的TNBC患者实现了客观肿瘤反应 ，该研究将 再招募10名患者。如果6名或更多患者（共25名）在3天内有客观肿瘤缓解， 在开始治疗几个月后，我们将与FDA会面，讨论患者注册试验的设计。 因三硝基甲烷导致的脑转移瘤影响-成功完成这些研究将建立 为后续的3期临床试验奠定基础。如果QBS-72 S被证明对治疗患者的脑转移瘤有效， 对于TNBC，它将是第一种可专门用于该人群的化疗剂。结果 有效性还支持进一步探索使用QBS-72 S治疗其他脑转移瘤患者 癌症，包括肺癌和黑素瘤。此外，由于LAT 1在许多其他形式的细胞中高度表达， 对于侵袭性癌症，QBS-72 S可能适用于治疗全身性癌症和CNS转移， 特别是在像TNBC这样的疾病中，几乎没有治疗选择。

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.