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——在 NCI 资助的 I 期和 II 期 SBIR 的支持下，Quadriga Biosciences 开发了 QBS-72S，这是一种新型化合物，旨在治疗多形性胶质母细胞瘤 (GBM)，即使是 60% 的患者 对替莫唑胺（TMZ）耐药的患者，目前的临床前研究表明。 QBS-72S满足全球有效的GBM治疗的三个要求：1）它具有细胞毒性机制 不受负责 TMZ 耐药性的 DNA 修复机制影响的作用，2) 它渗透 血脑屏障 (BBB)，3) 它以 GBM 为目标，同时不影响正常组织的进一步发育和发展。 QBS-72S 的商业化有可能提供第一种有效改善改善的药物 所有 GBM 患者（包括大多数对药物有耐药性的患者）的总生存期 当 O6- 时，新诊断和复发性 GBM 都会出现对 TMZ 的耐药性。 甲基鸟嘌呤-DNA-甲基转移酶 (MGMT) 可修复 TMZ 规避的 DNA 损伤。 这种对氮芥（N-芥末）的抵抗力会通过产生大量链间来损害 DNA 活跃分裂细胞中的交联 (ICL) ICL 的数量压倒了修复机制和依赖性。 许多有效的化疗药物都具有这些特征，但大多数都具有这些特征。 它们被 BBB 排除，相反，QBS-72S 通过 LAT-1（一种）选择性地穿过 BBB。 转运蛋白在肿瘤细胞中也高表达，但在健康组织中不表达，这些特征使得 QBS-72S 成为可能。 治疗 GBM 的理想候选者，一项首次人体研究正在进行中，以确认安全性并建立 在与 NCI 进行广泛讨论后，Quadriga 建议使用该阶段。 IIB SBIR 将 QBS-72S 作为新武器加入创新胶质母细胞瘤治疗的个体化筛选试验 (INSIGhT)，一项正在进行的、多中心、适应性 2 期临床试验，旨在证明安全性和有效性 评估当前标准治疗方案中替代 TMZ 的新疗法。 QBS-72S 替代 TMZ 改善总生存期和无进展生存期的有效性 具有未甲基化 MGMT 启动子的新诊断 GBM 患者 里程碑：1) 招募患者。 并完成研究——a) QBS-72S 组招募最多 70 名患者，TMZ 组招募最多 70 名患者，b) QBS-72S 手臂没有因无效而掉落，c) 治疗后 30 天随访 30%；2) 证明疗效——a) 总体 QBS-72S（主要终点）的生存风险比 ≥ 0.6，b) 无进展生存风险比 ≥ 0.6 QBS-72S（二级）；3) 表征安全性——没有意外的剂量限制毒性；4) 确定是否 确定的生物标志物预测 QBS-72S 的益处——探索性 5) 完成数据分析，准备第 3 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进行。 3 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。 无论 MGMT 状态如何，对于 GBM 都是有效的，并且可以建立新的、更有效的护理标准。