Translational Clinical Trials in Neuro-Oncology

神经肿瘤学转化临床试验

• 批准号: 7063172
• 负责人: DAVID A REARDON
• 金额: $ 34.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7063172
• 关键词: biotin; brain neoplasms; camptothecin; clinical research; clinical trial phase I; combination cancer therapy; drug administration routes; exotoxins; glioma; human subject; human therapy evaluation; immunoconjugates; infection related neoplasm /cancer; medulloblastoma; melphalan; meningitis; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; quality of life; radiation therapy dosage

The outcome for patients with primary malignant brain tumors remains dismal. Most progression occurs at the primary site despite conventional surgery and radiation therapy +/- chemotherapy. Therefore local control is the critical first step to improve outcome. In addition to the infiltrating destruction caused by these tumors, the non-specific nature of current therapies inevitably contributes to normal brain injury, further clinical decline and compromised quality of life. In response to the dire need for effective, innovative therapies for patients for malignant brain tumors, our center has developed novel therapeutics aimed at tumor-associated molecular targets, including unarmed, radiolabeled and toxin-conjugated monoclonal antibodies (MAbs), MAb fragments and growth factor ligand-toxin conjugates. During the prior SRC grant period, our Phase I and II clinical trials with radiolabeled MAbs, MAb fragments, and toxin conjugates confirmed that such therapeutics are effective and were associated with limited toxicity for both malignant glioma and neoplastic meningitis. Coupled with our goal of achieving local control, we have also completed extensive preclinical and clinical studies to improve systemic therapies, such as overcoming alkylguanine transferase (AGT)-mediated chemoresistance, to ultimately reach all tumor cells throughout the neuraxis. Our HYPOTHESIS is that novel therapeutics aimed at molecular targets will improve local tumor control and when coupled with more effective systemic therapies, ultimately contribute to overall tumor cell eradication while preserving quality of life for patients with malignant brain tumors. The SPECIFIC AIMS of this proposal are: Specific Aim 1. To conduct Phase I and II clinical trials to assess anti-tumor activity and toxicity of: 1) newly developed, tumor-targeted therapeutics against EGFRvIII, GPNMB, MRP3, and the glioma-associated gangliosides 3'-isoLM1 and 3',6'-isoLD1; 2) radioimmunotherapy with lutetium-177; 3) an oncolytic polio/rhinovirus recombinant; and 4) inhibitors of BCNU-induced DNA interstrand crosslink repair. Specific Aim 2. To determine the impact on quality of life of therapeutics evaluated in clinical trials of this project.

原发性恶性脑肿瘤患者的结果仍然令人沮丧。尽管进行常规手术和放射治疗+/-化疗，但大多数进展发生在原发部位。因此，局部控制是改善结果的关键的第一步。除了这些肿瘤造成的浸润性破坏外，当前治疗的非特异性性质不可避免地会导致正常脑损伤、进一步的临床衰退和生活质量下降。为了满足恶性脑肿瘤患者对有效、创新疗法的迫切需求，我们中心开发了针对肿瘤相关分子靶点的新型疗法，包括非武装、放射性标记和毒素偶联的单克隆抗体（MAb）， MAb 片段和生长因子配体-毒素缀合物。在之前的 SRC 资助期间，我们对放射性标记的 MAb、MAb 片段和毒素缀合物进行的 I 期和 II 期临床试验证实，此类疗法对于恶性胶质瘤和肿瘤性脑膜炎是有效的，并且毒性有限。结合我们实现局部控制的目标，我们还完成了广泛的临床前和临床研究，以改善全身治疗，例如克服烷基鸟嘌呤转移酶（AGT）介导的化疗耐药性，以最终到达整个神经轴的所有肿瘤细胞。我们的假设是，针对分子靶标的新疗法将改善局部肿瘤控制，并且当与更有效的全身疗法相结合时，最终有助于整体根除肿瘤细胞，同时保留 恶性脑肿瘤患者的生活质量。该提案的具体目标是： 具体目标 1. 进行 I 期和 II 期临床试验，以评估以下药物的抗肿瘤活性和毒性： 1) 新开发的针对 EGFRvIII、GPNMB、MRP3 和神经胶质瘤的肿瘤靶向治疗药物相关神经节苷脂 3'-isoLM1 和 3',6'-isoLD1； 2）镥177放射免疫治疗； 3) 溶瘤脊髓灰质炎/鼻病毒重组体； 4) BCNU 诱导的 DNA 链间交联修复抑制剂。 具体目标 2. 确定本项目临床试验中评估的治疗方法对生活质量的影响。