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

BMX-001 作为治疗高级别胶质瘤的治疗剂

• 批准号: 8904217
• 负责人: James D Crapo
• 金额: $ 97.64万
• 依托单位: BIOMIMETIX JV, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904217
• 关键词: Adjuvant; Adult; Affect; BMX gene; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Patient; Chemistry; Clinical Trials; Cognition; Cranial Irradiation; Deterioration; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease Progression; Dose; Drug Formulations; Drug Kinetics; Excision; Glioblastoma; Glioma; Goals; Hair; Hippocampus (Brain); Human; Impaired cognition; Impairment; Investments; Joint Ventures; Magnetic Resonance Imaging; Malignant Neoplasms; Manganese; Maximum Tolerated Dose; Metalloporphyrins; Nervous System Physiology; Nervous system structure; Neuraxis; Newly Diagnosed; Normal tissue morphology; Nuclear; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Primary Brain Neoplasms; Progression-Free Survivals; Radiation; Radiation induced damage; Radiation therapy; Radiation-Sensitizing Agents; Radio; Randomized; Reactive Oxygen Species; Resistance; Safety; Series; Small Business Innovation Research Grant; Stem cells; Stress; Testing; Therapeutic; Therapeutic Agents; Toxicology; Treatment Protocols; Up-Regulation; base; brain tissue; cancer diagnosis; chemotherapy; drug quality; health related quality of life; human subject; improved; killings; neurotoxicity; next generation; open label; preclinical safety; preclinical study; prevent; primary outcome; public health relevance; response; scale up; secondary outcome; stability testing; standard of care; temozolomide; transcription factor; treatment response; tumor; white matter; white matter damage

 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.

 描述(申请人提供)：一种新型氧化还原活性药物的1期和2期临床试验计划用于治疗高级别胶质瘤(WHO分级为III级和IV级)。该项目将测试一种化合物，这种化合物可以穿越血脑屏障，防止放射治疗(RT)后海马区干细胞丢失和白质降解。该化合物还可以抑制放疗后的肿瘤再生长，因此具有保护正常组织和改善肿瘤治疗反应的双重作用。这种药物既对RT具有神经保护作用，又是一种放射增敏剂，有望通过RT加强对胶质母细胞瘤的抑制。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，并与严重致残的中枢神经系统相关。认知和神经功能在诊断和治疗过程中受到损害。对新诊断的高级别胶质瘤的标准治疗包括手术切除，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肿瘤--胶质母细胞瘤(WHO IV级)的患者都死于疾病进展；中位生存期为确诊后9-15个月。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，下一代治疗原发脑肿瘤的一个主要要求是更有效地控制肿瘤并保护其免受神经毒性。这项提议的项目的目的是检验一种新的氧化还原活性金属卟啉是脑组织中有效的辐射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联合标准RT和TMZ的第一阶段临床试验，以及2)在新诊断的高级别胶质瘤患者中进行该新药联合标准RT和TMZ与单独使用标准RT和TMZ的随机开放标签第二阶段临床试验。主要结果是保护/改善认知。这种新型药物有可能防止认知能力的恶化，并改善高级别胶质瘤患者与健康相关的生活质量。 接受放射治疗和化疗，同时也提高了患者的存活率。