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

项目摘要/摘要 一种新型氧化还原活性药物的随机、概念验证、2期临床试验 建议在160名接受高级别胶质瘤初级治疗(世卫组织III级和IV级)的受试者中使用。 在先前的第二阶段SBIR下，第一阶段临床试验已经完成，并建立了 此二期临床试验使用的推荐剂量。该项目将测试一种化合物，在 动物，已被证明可以穿越血脑屏障，防止海马体干细胞丢失 和放射治疗(RT)后的脑白质退化。该化合物还能增强对肿瘤的杀伤力。 与放射治疗相结合，具有保护正常组织的双重效果 提高肿瘤治疗反应。这种药物对RT既有神经保护作用，也有望 RT增强对胶质母细胞瘤的抑制作用。原发脑瘤占所有确诊癌症的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。 与严重致残的中枢神经系统相关。认知与神经学 在诊断和治疗过程中，功能会受到损害。新诊断病例的护理标准 高级别胶质瘤需要手术切除，然后同步应用替莫唑胺(TMZ)进行放疗。 尽管进行了积极的治疗，但几乎所有患有最常见的成人原发脑瘤的患者， 胶质母细胞瘤(WHO IV级)，死于疾病进展；中位生存期为12-16个月 诊断。大多数高级别胶质瘤对目前可用的治疗方法都有抵抗力。因此，一项主要要求是- 为下一代治疗原发性脑肿瘤提供更有效的肿瘤控制、保护 抗神经毒性，减少骨髓抑制(即血栓形成)的发生率。 细胞减少症)。在这个SBIR阶段IIB桥奖中提出的第二阶段临床试验是为了测试 假设一类新的氧化还原活性金属卟啉中的先导化合物BMX-001将 延长患者生存时间，同时保护正常组织，提高生活质量。这个 具体目标是：1)通过完成一项随机的、开放的- BMX-001联合标准RT和TMZ治疗初诊患者的LABELⅡ期临床试验 高级别胶质瘤患者(160名受试者，1：1随机)，以及2)证实了副作用的保护 通过评估认知、白质完整性、生活质量(HRQOL)和骨骼来评估放化疗 保护骨髓。主要结果是：1)基于总生存率和无进展生存率的疗效； 2)保护/改善认知；3)肿瘤的放射反应；4)保护骨骼 骨髓抗化疗引起的血小板减少症。探索性结果是1)HRQOL和 2)脑白质完整性(MRI脑扩散张量成像)。

PROJECT SUMMARY/ABSTRACT A randomized, proof-of-concept, Phase 2 clinical trial of a new class of redox-active pharmaceutical is proposed in 160 subjects undergoing primary treatment for high-grade glioma (WHO grade III and IV). Under a prior Phase II SBIR, a Phase 1 clinical trial has been completed with establishment of the recommended dose being used for this Phase 2 clinical trial. This project will test a compound that, in animals, has been demonstrated to cross the blood-brain barrier and prevent hippocampal stem cell loss and white matter degradation following radiation therapy (RT). The compound also enhances tumor killing in combination with radiation therapy and thus has the dual impact of protecting normal tissues while improving tumor treatment responses. This drug is both neuroprotective against RT and 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 12-16 months after diagnosis. Most high-grade gliomas are resistant to current available therapies. Thus, a major require- ment for the next generation therapy of primary brain tumors is more effective tumor control, protection against neurotoxicity, and reduction in the incidence of bone marrow suppression (i.e., thrombo- cytopenia). The Phase 2 clinical trial proposed in this SBIR Phase IIB Bridge Award is to test the hypothesis that BMX-001, the lead compound in a new class of redox-active metalloporphyrins, will extend patient survival and at the same time protect normal tissues and enhance quality of life. The specific aims are to: 1) confirm enhanced survival (tumor control) by completing a randomized, open- label Phase 2 clinical trial of BMX-001 in combination with standard RT and TMZ in newly diagnosed high-grade glioma patients (160 subjects, 1:1 randomization), and 2) confirm protection from side effects of radiochemotherapy by assessing cognition, white matter integrity, quality of life (HRQoL) and bone marrow protection. The primary outcomes are 1) Efficacy based on overall and progression-free survival; 2) Protection/improvement of cognition; 3) Radiographic response of tumor; and 4) Protection of bone marrow against chemotherapy-induced thrombocytopenia. Exploratory outcomes are 1) HRQoL and 2) White matter integrity (MRI brain diffusion tensor imaging).