BMX-001 as a Therapeutic Agent for Treatment of High-Grade Gliomas

 描述（由申请人提供）：拟在高级别胶质瘤（WHO III级和IV级）中进行一类新的氧化还原活性药物的I期和II期临床试验。该项目将测试一种化合物，该化合物可以穿过血脑屏障，防止放射治疗（RT）后海马干细胞丢失和白色物质降解。该化合物还抑制RT后的肿瘤再生长，因此具有保护正常组织同时改善肿瘤治疗反应的双重影响。这种药物既对RT具有神经保护作用，又是一种放射增敏剂，有望增强RT对胶质母细胞瘤的抑制作用。原发性脑肿瘤占所有诊断癌症的1%。尽管这些肿瘤是一种罕见的恶性肿瘤，但高级别胶质瘤具有侵袭性和致命性，并伴有严重的中枢神经系统受累。认知和神经功能在诊断和治疗期间受到损害。新诊断的高级别胶质瘤的标准治疗包括手术切除，然后进行RT和同时进行替莫唑胺（TMZ）。尽管进行了积极的治疗，但几乎所有最常见的成人原发性脑肿瘤-胶质母细胞瘤（WHO IV级）患者都死于疾病进展;诊断后的中位生存期为9-15个月。大多数高级别神经胶质瘤对目前可用的疗法具有抗性。因此，原发性脑肿瘤的下一代治疗的主要要求是需要更有效的肿瘤控制和针对神经毒性的保护。该拟议项目的目的是测试一类新的氧化还原活性金属卟啉是脑组织中有效的无线电保护剂和肿瘤增敏剂的假设。具体目标是：1）在新诊断的高级别胶质瘤患者中进行该新药与标准RT和TMZ组合的I期临床试验，以及2）在新诊断的高级别胶质瘤患者中进行该新药与标准RT和TMZ组合对比标准RT和TMZ单独的随机开放标签II期临床试验。主要结局是保护/改善认知。这种新型药物有可能防止高级胶质瘤患者的认知恶化并改善健康相关的生活质量 接受RT和化疗，同时也提高了患者的生存率。

 DESCRIPTION (provided by applicant): Phase 1 and Phase 2 clinical trials of a new class of redox-active pharmaceutical are proposed in high-grade glioma (WHO grade III and IV). This project will test a compound that crosses the blood-brain barrier and which prevents hippocampal stem cell loss and white matter degradation following radiation therapy (RT). The compound also inhibits tumor regrowth following RT and thus has the dual impact of protecting normal tissues while improving tumor treatment responses. This drug is both neuroprotective against RT and a radio sensitizer that is expected to enhance inhibition of glioblastoma by RT. Primary brain tumors represent 1% of all diagnosed cancers. Even though these tumors represent a rare malignancy, high-grade gliomas are aggressive and lethal and are associated with severe disabling central nervous system involvement. Cognition and neurological function are compromised at diagnosis and during treatment. The standard of care for newly diagnosed high-grade gliomas involves surgical resection, followed by RT with concurrent temozolomide (TMZ). Despite aggressive treatment, nearly all patients with the most common form of adult primary brain tumor, glioblastoma (WHO grade IV), die of disease progression; median survival is 9-15 months after diagnosis. Most high-grade gliomas are resistant to current available therapies. Thus, a major requirement for the next generation therapy of primary brain tumors requires more effective tumor control and protection against the neurotoxicity. The objective of this proposed project is to test the hypothesis that a new class of redox-active metalloporphyrins is an effective radio protector and tumor sensitizer in brain tissue. The specific aims are to: 1) perform a Phase 1 clinical trial of this new drug in combination with standard RT and TMZ in newly diagnosed high-grade glioma patients, and 2) perform a randomized open-label Phase 2 clinical trial of the new drug in combination with standard RT and TMZ versus standard RT and TMZ alone in patients with newly diagnosed high-grade glioma patients. The primary outcome is protection/improvement of cognition. This new class of drug has the potential to protect against deterioration of cognition and improve health-related quality of life in high-grade glioma patients undergoing RT and chemotherapy, while also enhancing patient survival.