Phase 1b/2a Trial of QBS-72S for the Treatment of Newly Diagnosed Glioblastoma Multiforme in Patients with Unmethylated MGMT Promoters

QBS-72S 治疗 MGMT 启动子未甲基化的新诊断多形性胶质母细胞瘤患者的 1b/2a 期试验

• 批准号: 10248080
• 负责人: Gordon M Ringold
• 金额: $ 136.82万
• 依托单位: QUADRIGA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248080
• 关键词: Accounting; Address; Adjuvant; Aftercare; Amendment; American; Biological Sciences; Blood - brain barrier anatomy; Cells; Chemicals; Clinical Trials Design; DNA Damage; DNA Repair; DNA repair methyltransferase; Data Analyses; Development; Diagnosis; Disease; Dose; Dose-Limiting; Enrollment; Excision; Funding; Futility; Glioblastoma; Glioma; Human; MGMT gene; Malignant neoplasm of brain; Mechlorethamine; Mustard; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Pathway interactions; Patient Recruitments; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Progression-Free Survivals; Protocols documentation; Radiation therapy; Recurrence; Regimen; Research; Resistance; Safety; Site; Small Business Innovation Research Grant; Testing; Therapeutic; Therapy trial; Tissues; Toxic effect; Tumor Tissue; arm; brain tissue; commercialization; crosslink; cytotoxic; design; effectiveness evaluation; first-in-human; follow-up; hazard; improved; improved outcome; innovation; neoplastic cell; novel; novel therapeutics; phase III trial; preclinical study; predictive marker; prevent; primary endpoint; programs; promoter; recruit; repaired; resistance mechanism; response; screening; standard of care; temozolomide; therapy design; tumor

PROJECT SUMMARY—With support from NCI-funded Phase I and Phase II SBIRs, Quadriga Biosciences developed QBS-72S, a novel compound designed to treat glioblastoma multiforme (GBM), even in the 60% of patients who are resistant to temozolomide (TMZ), the current standard of care. Preclinical studies demonstrated QBS-72S meets the three requirements for a globally effective GBM treatment: 1) it has a cytotoxic mechanism of action that is not affected by the DNA repair mechanisms responsible for resistance to TMZ, 2) it penetrates the blood brain barrier (BBB), and 3) it targets GBM while sparing normal tissue. Further development and commercialization of QBS-72S has the potential to deliver the first drug that is effective for improving overall survival in all patients with GBM, including the majority of patients who are resistant to the current standard of care. Resistance to TMZ in both newly-diagnosed and recurrent GBM occurs when O6- methylguanine-DNA-methyltransferase (MGMT) repairs DNA damage produced by TMZ. QBS-72S circumvents this resistance with a nitrogen mustard (N-mustard) that damages DNA by producing numerous inter-strand crosslinks (ICLs) in actively dividing cells. The number of ICLs overwhelms repair mechanisms, and the reliance on cellular division limits off-target toxicity. Many effective chemotherapeutics share these features, but most of them are excluded by the BBB. In contrast, QBS-72S is selectively transported across the BBB by LAT-1, a transporter that is also highly expressed in tumor cells but not in healthy tissues. These features make QBS-72S an ideal candidate for treating GBM, and a first-in-humans study is underway to confirm safety and establish a recommended Phase 2 dose. Following extensive discussions with NCI, Quadriga proposes to use this Phase IIB SBIR to add QBS-72S as a new arm to the INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT), an ongoing, multi-site, adaptive Phase 2 clinical trial designed to demonstrate the safety and efficacy of novel therapeutics as replacements for TMZ in the current standard of care regimen. Aim. Evaluate the effectiveness of QBS-72S in place of TMZ for improving overall survival and progression-free survival in patients with newly diagnosed GBM with unmethylated MGMT promoters. Milestones: 1) recruit patients and complete study—a) recruit up to 70 patients in the QBS-72S arm and up to 70 in the TMZ arm, b) QBS-72S arm not dropped for futility, c) follow up with ³ 80% at 30 days post-treatment; 2) demonstrate efficacy—a) overall survival hazard ratio ≥ 0.6 for QBS-72S (primary endpoint), b) progression-free survival hazard ratio ≥ 0.6 for QBS-72S (secondary); 3) characterize safety—no unexpected dose-limiting toxicities; 4) determine whether defined biomarkers predict QBS-72S benefit—exploratory; 5) complete data analysis, prepare Phase 3 protocol, and submit IND amendment. Impact: Successful completion of these milestones is required to proceed to a Phase 3 trial. Successful completion of a Phase 3 trial and receipt of FDA approval would provide the first drug for GBM that is effective regardless of MGMT status and could establish a new, more effective standard of care.

项目摘要 - NCI资助的I期和II期SBIRS的支持，Quadriga Biosciences 开发的QBS-72s是一种新型化合物，旨在处理多形胶质母细胞瘤（GBM），即使在60％ 抗替莫唑胺（TMZ）的患者是当前的护理标准。临床前研究证明 QBS-72符合全球有效GBM治疗的三个要求：1）它具有细胞毒性机制 不受负责TMZ抗性的DNA修复机制影响的动作，2）它穿透了 血液脑屏障（BBB）和3）在保留正常组织时靶向GBM。进一步发展和 QBS-72S的商业化有可能提供有效改进的第一种药物 所有GBM患者的总体生存期，包括大多数耐药的患者 当前的护理标准。在O6-- TMZ产生的DNA损伤。 QBS-72S绕行 这种耐氮芥末（N-mustard）通过产生大量股间损坏DNA的耐药性 在主动分裂细胞中的交联（ICL）。 ICL的数量压倒性修复机制和浮雕 在细胞分裂上限制了靶向毒性。许多有效的化学治疗剂共享这些功能，但大多数 它们被BBB排除在外。相比之下，QBS-72s通过LAT-1选择性地跨BBB运输 转运蛋白在肿瘤细胞中也高度表达，但在健康组织中不表达。这些功能使QBS-72s 一个理想的治疗GBM的候选人，正在进行第一届人类研究以确认安全并建立一个 推荐的2阶段剂量。在与NCI进行了广泛的讨论之后，Quadriga提出了使用此阶段的提议 IIB SBIR将QBS-72添加为新的手臂，以进行创新的胶质母细胞瘤疗法的个性化筛查试验 （Insight）是一项持续的多站点，自适应阶段2临床试验，旨在证明安全性和效率 在当前护理方案中，新型疗法作为TMZ的替代。目的。评估 QBS-72代替TMZ的有效性，以提高整体生存和无进展生存率 新诊断为使用未甲基化的MGMT启动子的GBM的患者。里程碑：1）招募患者 和完整的研究 - A）在QBS-72臂中最多招募70名患者，在TMZ ARM中最多可招募70例，b）QBS-72S 手臂未掉落以进行能量，c）在处理后30天后进行六80％的跟进； 2）展示效率 - A）总体 QBS-72s（主要终点）的生存危险比≥0.6，b）无进展生存危险比≥0.6≥0.6 QBS-72S（次要）; 3）表征安全性 - 没有意外的剂量限制性毒性； 4）确定是否 定义的生物标志物预测QBS-72的好处 - 探索； 5）完成数据分析，准备第3阶段协议， 并提交IND修正案。影响：成功完成这些里程碑必须进行 第三阶段试验。成功完成3阶段试验和FDA批准的收到将提供第一种药物 对于有效的GBM，无论MGMT状态如何，都可以建立一个新的，更有效的护理标准。