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。尽管传统的手术和放射疗法+/-化学疗法，但大多数进展发生在主要部位。因此，地方控制是改善结果的关键第一步。除了由这些肿瘤造成的浸润破坏外，当前疗法的非特异性性质不可避免地导致正常的脑损伤，进一步的临床下降和生活质量损害。为了应对对恶性脑肿瘤患者的有效，创新疗法的迫切需求，我们的中心开发了针对肿瘤相关的分子靶标的新型治疗剂，包括未武装，放射性标记和与毒素偶联的单克隆抗体（MABS），，MABS（MABS），，，，， MAB片段和生长因子配体 - 毒素结合物。在先前的SRC批准期间，我们的I期和II期临床试验具有放射性标记的mAb，mAb片段和毒素偶联物证实，这种治疗剂是有效的，并且对恶性神经胶质瘤和肿瘤性脑膜炎的毒性有限。再加上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，以改善全身疗法，例如克服烷基圭氨酸转移酶（AGT）介导的化学固定剂，最终在整个神经动物的整个神经疗法中最终到达所有肿瘤细胞。我们的假设是，针对分子靶标的新型治疗剂将改善局部肿瘤的控制，并与更有效的全身疗法相结合，最终有助于消除整体肿瘤细胞 恶性脑肿瘤患者的生活质量。该提议的具体目的是：具体目的1。进行I和II期临床试验，以评估以下方面的抗肿瘤活性和毒性：1）针对EGFRVIII，GPNMB，MRP3，MRP3，胶质瘤相关的3'- ISOLM1和3'- ISOLM1和3'-ISOLM1和3'，6'-ISOLD1； 2）lutetium-177的放射免疫疗法； 3）溶瘤性脊髓灰质炎/鼻病毒重组； 4）BCNU诱导的DNA链链交联修复的抑制剂。 具体目标2。确定该项目临床试验中评估的治疗剂生活质量的影响。