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

项目摘要-在NCI资助的第一阶段和第二阶段SBIRS的支持下，Quadriga Biosciences 对替莫唑胺(TMZ)耐药的患者，这是目前的治疗标准。临床前研究表明 QBS-72S符合全球有效的GBM治疗的三个要求：1)它具有细胞毒机制 不受导致抗TMZ的DNA修复机制影响的作用，2)它穿透 血脑屏障(BBB)，以及3)它以GBM为靶标，而不损害正常组织。进一步发展和 QBS-72的商业化有可能提供第一种有效改善病情的药物 所有GBM患者的总存活率，包括大多数对 目前的护理标准。新诊断和复发的GBM对TMZ的耐药性发生在O6- 甲基鸟嘌呤-DNA-甲基转移酶(MGMT)修复TMZ引起的DNA损伤。QBS-72S规避 这种对氮芥子(N-芥子)的抗性会通过产生大量的间链来破坏DNA 活跃分裂细胞中的交联链(ICL)。ICL的数量超过了修复机制，以及对 对细胞分裂的影响限制了非靶标毒性。许多有效的化疗药物都有这些特点，但大多数 他们被BBB排除在外。相比之下，QBS-72由LAT-1有选择地通过BBB传输， 转运蛋白在肿瘤细胞中也高表达，但在健康组织中不表达。这些特点使QBS-72 是治疗GBM的理想候选者，一项首例人类研究正在进行中，以确认安全性并建立 推荐的第二阶段剂量。在与NCI进行了广泛的讨论后，Quadriga提议使用此阶段 IIB SBIR将QBS-72S作为新的手臂加入创新的胶质母细胞瘤治疗的个体化筛查试验 (Insight)，这是一项正在进行的多站点适应性第二阶段临床试验，旨在展示安全性和有效性 在目前的护理方案标准中，新疗法作为TMZ的替代品。瞄准。评估 QBS-72替代TMZ改善小鼠总生存期和无进展生存期的疗效 新诊断的具有未甲基化MGMT启动子的GBM患者。里程碑：1)招募病人 和完整的研究-a)在QBS-72S组招募多达70名患者，在TMZ组招募多达70名患者，b)QBS-72S 手臂没有因无效而掉落，c)在治疗后30天进行80%的随访；2)证明疗效-a)总体 QBS-72S(主要终点)的生存风险比≥为0.6，b)无进展生存风险比≥为0.6 QBS-72S(次级)；3)表征安全性--没有意外的剂量限制毒性；4)确定 已定义的生物标志物预测QBS-72S益处-探索性；5)完成数据分析，准备第三阶段方案， 并提交IND修正案。影响：需要成功完成这些里程碑，才能继续 第三阶段试验。成功完成3期试验并获得FDA批准将提供第一种药物 对于GBM，无论MGMT状态如何，这都是有效的，并可以建立一个新的、更有效的护理标准。

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.