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

项目总结/摘要 一项关于一类新的氧化还原活性药物的随机、概念验证、2期临床试验， 在160例接受高级别胶质瘤（WHO III级和IV级）初级治疗的受试者中提出。 根据之前的II期SBIR，已经完成了1期临床试验， 本II期临床试验使用的推荐剂量。该项目将测试一种化合物， 动物，已被证明可以穿过血脑屏障，防止海马干细胞丢失 和放射治疗（RT）后的白色物质降解。该化合物还能增强肿瘤杀伤力 并因此具有保护正常组织的双重作用， 改善肿瘤治疗反应。这种药物对RT具有神经保护作用， 通过RT增强胶质母细胞瘤的抑制。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 并且与严重的中枢神经系统损伤有关。认知和神经 功能在诊断和治疗过程中受到损害。新诊断的标准治疗 高级别神经胶质瘤涉及手术切除，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.大多数高级别神经胶质瘤对目前可用的疗法具有抗性。因此，一个主要的要求- 下一代肿瘤治疗方案对原发性脑肿瘤更有效的控制、保护 抗神经毒性，和降低骨髓抑制的发生率（即，血栓，血栓 血细胞减少症）。SBIR Phase IIB Bridge Award中提出的2期临床试验旨在测试 假设BMX-001，一类新的氧化还原活性金属卟啉的先导化合物， 延长患者生存期，同时保护正常组织并提高生活质量。的 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治疗新诊断糖尿病患者的标签2期临床试验 高级别胶质瘤患者（160名受试者，1：1随机化），和2）证实了对副作用的保护 通过评估认知、白色物质完整性、生活质量（HRQoL）和骨 骨髓保护主要结局是1）基于总体生存期和无进展生存期的疗效; 2)保护/改善认知; 3）肿瘤的放射学反应;和4）保护骨 骨髓对化疗引起的血小板减少症。探索性结局为1）HRQoL和 2)白色物质完整性（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).