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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 Quadriga Biosciences 的新型小分子治疗药物 QBS-72S 将 DNA 烷基化部分与一种氨基酸类似物，利用 L 型氨基酸转运蛋白 1 (LAT1) 实现跨转运临床前研究的结果表明，血脑屏障（BBB）和肿瘤细胞中的选择性积累。 QBS-72S 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，TNBC 患者脑转移的治疗仅限于。由于面临以下挑战，手术干预或放射治疗以及药物开发均未成功在这个直接进入第二阶段的 SBIR 中，Quadriga 提议进行一项跨 BBB 运输有效药物的研究。对 TNBC 引起的脑转移患者进行 2a 期概念验证临床试验，以测试安全性和使用西蒙两阶段设计的 QBS-72S 的功效预计将为设计提供信息。一项关键的 3 期试验旨在评估 QBS-72S 在 TBNC 患者中的安全性和有效性。斯坦福大学的医生将鉴定出多达 25 名患有 TNBC 和脑转移的患者。及其基于大脑对比 MRI 的转诊网络将给予参与者最大程度的治疗。每四周静脉注射一次 QBS-72S 的耐受剂量 (MTD)，持续长达 2 年。将在前四个月和每隔一个月每次给药前一天通过 MRI 进行评估此后的主要终点是客观缓解率（即生长≤ 25% 的患者百分比）。 3 个月时肿瘤大小变化、肿瘤大小无变化或肿瘤大小减小）包括。总生存期、无进展生存期、全身性疾病的反应、不良事件和变化实验室评估的患者参数：使用西蒙的两阶段 Minimax 设计（如果有两个或多个）。前 15 名接受 QBS-72S 治疗的可评估 TNBC 患者实现了客观的肿瘤缓解，该研究将如果 6 名或更多患者（总计 25 名）在 3 天内出现客观肿瘤反应，则再招募 10 名患者。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与 TNBC 产生的脑代谢综合征有关——这些研究的成功完成将确定如果 QBS-72S 被证明能有效治疗患者的脑转移，则为后续的 3 期临床试验奠定基础。与 TNBC 一起，这将是第一个专门针对该人群的化疗药物。疗效还将支持进一步探索使用 QBS-72S 治疗其他脑转移患者此外，由于 LAT1 在许多其他形式中高度表达。对于侵袭性癌症，QBS-72S可能适用于治疗全身性癌症和中枢神经系统转移，尤其是像 TNBC 这样的疾病，治疗选择很少。