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

QBS10072S 用于治疗脑转移性三阴性乳腺癌

• 批准号: 10478212
• 负责人: Gordon M Ringold
• 金额: $ 28.65万
• 依托单位: QUADRIGA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478212
• 关键词: Adverse event; Affect; African American; Alkylating Agents; Amino Acid Transporter; Amino Acids; Biological Sciences; Blood - brain barrier anatomy; Brain; Breast Cancer Patient; Clinical Trials; DNA; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Enrollment; Evaluable Disease; Foundations; Funding; Growth; Human; In Vitro; Length; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Modeling; Mus; Neoplasm Metastasis; Nervous System Physiology; Network-based; Normal tissue morphology; Operative Surgical Procedures; Participant; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Physicians; Population; Process; Progression-Free Survivals; Quality of life; Radiation therapy; Safety; Small Business Innovation Research Grant; Systemic disease; Therapeutic; Therapeutic Intervention; Universities; Woman; Xenograft Model; Xenograft procedure; analog; blood-brain barrier crossing; blood-brain tumor barrier; cancer type; chemotherapeutic agent; commercialization; design; drug development; improved; indexing; intravenous administration; malignant breast neoplasm; melanoma; neoplastic cell; objective response rate; phase III trial; preclinical study; preservation; primary endpoint; response; safety testing; secondary endpoint; small molecule; small molecule therapeutics; therapy development; triple-negative invasive breast carcinoma; tumor; tumor growth; young woman

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.

项目摘要 Quadriga Biosciences的新小分子疗法QBS-72S将DNA烷基化部分与 利用L型氨基酸转运蛋白1（LAT1）的氨基酸模拟 肿瘤细胞中的血脑屏障（BBB）和选择性积累。临床前研究的结果表明 QBS-72s可能对多种癌症类型引起的脑转移（脑转移）有效，包括 三重阴性乳腺癌（TNBC）。目前，TNBC患者的脑METS治疗仅限于 由于挑战 在整个BBB上运输有效的代理。在这个直接到相的II SBIR中，Quadriga提议进行 第2A阶段的概念验证临床试验对TNBC导致的脑MET患者的临床试验，以测试安全性和 QBS-72使用Simon的两阶段设计的功效。这项研究的数据有望告知 一个关键的3期试验。目的。评估QBS-72在TBNC患者中的安全性和效率 转移。斯坦福大学的医生将确定多达25例TNBC和大脑大都会的患者 并基于大脑的对比度MRI的推荐网络。参与者将得到最大对待 QBS-72的耐受剂量（MTD）每四个星期静脉内服用2年。肿瘤生长 将在每次管理前一天和每隔一个月通过MRI评估 此后。主要终点是客观响应率（即，生长≤25％的患者百分比 肿瘤大小，肿瘤大小没有变化或肿瘤大小的减小）。次要终点包括 总体生存期，无进展生存期长度，全身性疾病的反应，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的两阶段最小设计，如果两个或更多 前15个评估了用QBS-72治疗的TNBC患者达到了客观肿瘤反应 ，这项研究将 注册10名患者。如果六名或更多患者（总计25例）在3中具有客观肿瘤反应 启动治疗后的几个月，我们将与FDA会面，讨论患者的注册试验的设计 由TNBC产生的脑MET。影响 - 成功完成这些研究将确定 后续3阶段临床试验的基础。如果QBS-72s证明有效治疗患者的脑METS 使用TNBC，这将是专门为该人群提供的第一个化学治疗剂。发现 效率还将支持进一步探索使用QBS-72s治疗其他脑转移的患者 癌症，包括肺癌和黑色素瘤。此外，由于LAT1在许多其他形式上都高度表达 在侵略性癌症中，QBS-72s可能适合治疗全身性癌症和中枢神经系统转移， 特别是在像TNBC这样的疾病中，几乎没有治疗选择。