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SBIR的支持下，Quadriga Biosciences 开发了QBS-72S，一种旨在治疗多形性胶质母细胞瘤（GBM）的新型化合物，即使在60%的 对替莫唑胺（TMZ）（目前的标准治疗）耐药的患者。临床前研究表明， QBS-72S符合全球有效GBM治疗的三个要求：1）具有细胞毒性机制 不受DNA修复机制的影响，负责对TMZ的抗性，2）它穿透 血脑屏障（BBB），和3）它靶向GBM而不影响正常组织。进一步发展和 QBS-72S的商业化有可能提供第一种有效改善 所有GBM患者的总生存期，包括大多数对GBM耐药的患者。 目前的护理标准。新诊断和复发性GBM对TMZ的耐药发生在O6- 甲基鸟嘌呤-DNA-甲基转移酶（MGMT）修复TMZ产生的DNA损伤。QBS-72S规避 这种耐药性与氮芥（N-芥末），破坏DNA产生大量的链间 在活跃分裂的细胞中的ICLs。ICLs的数量和ICLs的修复机制，以及ICLs的依赖性， 限制了脱靶毒性许多有效的化疗药物都具有这些特征，但大多数 它们被BBB排除在外。相比之下，QBS-72S通过LAT-1选择性地转运穿过BBB，LAT-1是一种免疫调节剂。 在肿瘤细胞中也高度表达，但在健康组织中不表达。这些特点使QBS-72S 是治疗GBM的理想候选药物，一项首次人体研究正在进行中，以确认安全性并建立 推荐的2期剂量。在与NCI进行广泛讨论后，Quadriga建议使用此阶段 IIB SBIR将QBS-72S作为一个新的分支添加到创新胶质母细胞瘤治疗的个体化筛选试验中 （INSIGhT），一项正在进行的、多中心、适应性2期临床试验，旨在证明 新疗法作为TMZ的替代品在目前的标准治疗方案。瞄准评价 QBS-72S替代TMZ改善患者总生存期和无进展生存期的有效性 新诊断的GBM患者，MGMT启动子未甲基化。关键：1）招募患者 并完成研究-a）QBS-72 S组招募最多70例患者，TMZ组招募最多70例患者，B）QBS-72 S 手臂未因无效而脱落，c）治疗后30天随访率≥ 80%; 2）证明疗效-a）总体 QBS-72 S的生存风险比≥ 0.6（主要终点），B）无进展生存风险比≥ 0.6（主要终点） QBS-72 S（次要）; 3）表征安全性-无非预期剂量限制性毒性; 4）确定是否 定义的生物标志物预测QBS-72S的益处-探索性; 5）完成数据分析，准备3期方案， 并提交IND修正案。影响：需要成功完成这些里程碑， 三期试验。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状态如何都有效，并且可以建立新的，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.