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: 10170294
• 负责人: James D Crapo
• 金额: $ 200万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170294
• 关键词: Adjuvant; Adjuvant Therapy; Adult; Affect; Alkylating Agents; Animal Model; Animals; BMX gene; Blood - brain barrier anatomy; Bone Marrow; Bone Marrow Suppression; Brain; Chemistry; Chemotherapy and/or radiation; Clinical Treatment; Clinical Trials; Cognition; Cranial Irradiation; Deterioration; Diagnosis; Diagnostic radiologic examination; Diffusion Magnetic Resonance Imaging; Disease Progression; Dose; Excision; Formulation; Funding; Genetic Transcription; Glioblastoma; Glioma; Goals; Hippocampus (Brain); Howard Temin Award; Human; Impaired cognition; Impairment; Incidence; Investments; Lead; Life; Magnetic Resonance Imaging; Metalloporphyrins; Nervous System Physiology; Neuraxis; Newly Diagnosed; Normal tissue morphology; Nuclear; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platelet Count measurement; Primary Brain Neoplasms; Progression-Free Survivals; Quality of life; Radiation Injuries; Radiation therapy; Randomized; Reactive Oxygen Species; Reporting; Resistance; Series; Serious Adverse Event; Small Business Innovation Research Grant; Stress; Testing; Therapeutic Agents; Thrombocytopenia; Time; Toxicology; Up-Regulation; aggressive therapy; base; brain tissue; cancer diagnosis; chemoradiation; chemotherapy; cognitive function; commercialization; drug quality; experience; health related quality of life; improved; mouse model; neoplastic cell; neurotoxicity; next generation; novel drug class; open label; phase I trial; phase II trial; preclinical safety; prevent; primary outcome; rare cancer; response; scale up; side effect; stability testing; standard of care; stem cells; temozolomide; transcription factor; treatment response; tumor; tumor growth; white matter; white matter damage

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).

项目概要/摘要 一项新型氧化还原活性药物的随机、概念验证 2 期临床试验是 提议在 160 名接受高级神经胶质瘤（WHO III 级和 IV 级）初级治疗的受试者中进行。 根据先前的 II 期 SBIR，随着建立了 本次 2 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并防止海马干细胞损失 放射治疗（RT）后白质退化。该化合物还增强肿瘤杀伤作用 与放射治疗相结合，因此具有保护正常组织的双重作用，同时 改善肿瘤治疗反应。该药物对 RT 具有神经保护作用，并且有望 增强 RT 对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 并与严重的中枢神经系统失能相关。认知和神经学 功能在诊断和治疗期间受到损害。新诊断的护理标准 高级别神经胶质瘤需要手术切除，然后同时进行放疗和替莫唑胺 (TMZ)。 尽管进行了积极的治疗，但几乎所有患有最常见形式的成人原发性脑肿瘤的患者， 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。大多数高级别神经胶质瘤对当前可用的疗法有抵抗力。因此，一个主要要求是—— 原发性脑肿瘤的下一代疗法是更有效的肿瘤控制、保护 对抗神经毒性，并减少骨髓抑制（即血栓形成）的发生率 血细胞减少症）。 SBIR IIB 期桥奖中提出的 2 期临床试验是为了测试 假设 BMX-001（一类新型氧化还原活性金属卟啉中的先导化合物）将 延长患者的生存期，同时保护正常组织并提高生活质量。这 具体目标是：1）通过完成随机、开放的试验来确认生存率（肿瘤控制）的提高 标签 BMX-001 联合标准 RT 和 TMZ 在新诊断中的 2 期临床试验 高级别神经胶质瘤患者（160 名受试者，1:1 随机化），以及 2) 确认可防止副作用 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 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； 4) 骨骼保护 骨髓对抗化疗引起的血小板减少症。探索性结果是 1) HRQoL 和 2）白质完整性（MRI脑扩散张量成像）。