CORE-3-PHASE I/II CLINICAL TRIALS

CORE-3-I/II 期临床试验

• 批准号: 6844183
• 负责人: DAVID A REARDON
• 金额: $ 17.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844183
• 关键词: antineoplastics; biomedical facility; brain neoplasms; clinical trial phase I; clinical trial phase II; enzyme inhibitors; human subject; human therapy evaluation; immunoconjugates; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research

]'he outcome for patients with primary malignant brain tumors remains dismal with over 90% of patients dying within 2 years of diagnosis. In this application we will focus on two major roadblocks to successful treatment for patients with these tumors. Response to chemotherapy is either non-existent or short-lived indicating that de novo or acquired resistance to chemotherapy is a critical contributor to poor outcome. In addition, the vast majority of patients recur locally indicating that local control remains elusive and represents a critical step to achieve a cure. To build upon our successful efforts to overcome chemoresistance mediated by AGT using the competitive inhibitor O6-BG, we will focus on two additional important mediators of chemoresistance including the DNA protectant glutathione-S-transferase (GSTP1) and the nuclear DNA repair enzyme poly(ADP-ribose) polymerase (PARP). In addition, our encouraging results with radiolabeled MAbs such as the anti-tenascin MAb 81 C6 or the EGFR-targeting toxin-conjugate TP-38, confirm that innovative tumor-targeting therapeutics can improve local control and improve overall outcome. We therefore will also evaluate additional novel therapeutics targeting recently identified tumor-associated markers such as EGFRvIII, glycoprotein NMB, multidrug resistant protein 3, the gliomaassociated cell-surface gangliosides 3'-isoLM1 and 3',6'-isoLD 1, human CMV and the poliovirus receptor CD155. Our HYPOTHESIS is that rationally designed, novel therapeutic strategies that either block key mediators of chemoresistance or that augment local control, will improve the survival of patients with malignant brain tumors while preserving an optimal quality of life. The Specific Aims of this proposal are: Specific Aim 1. To conduct Phase I and II clinical trials to assess the anti-tumor activity and safety of inhibitors of chemoresistance mediated by GSTP1 and PARP. Specific Aim 2. To conduct Phase I and II clinical trials to assess the anti-tumor activity and safety of innovative therapeutics designed to improve local control including radiolabeled MAbs, MAb fragments, toxin conjugates, DCs against tumor-associated CMV antigens and an oncolytie polio/rhinovirus recombinant. Specific Aim 3. To determine the impact of these therapeutic agents on overall quality of life for patients with malignant brain tumors.

]“原发性恶性脑肿瘤患者的结局仍然令人沮丧，超过 90% 的患者在诊断后 2 年内死亡。在此应用中，我们将重点关注成功治疗这些肿瘤患者的两个主要障碍。对化疗的反应要么不存在，要么持续时间短暂，表明对化疗的从头耐药或获得性耐药是导致不良结果的关键因素。此外，绝大多数患者会出现局部复发，这表明局部控制仍然难以捉摸，这是实现治愈的关键一步。为了利用竞争性抑制剂 O6-BG 成功克服 AGT 介导的化学耐药性，我们将重点关注另外两种重要的化学耐药性介质，包括 DNA 保护剂谷胱甘肽-S-转移酶 (GSTP1) 和核 DNA 修复酶聚 ( ADP-核糖）聚合酶（PARP）。此外，我们鼓励 放射性标记单克隆抗体（例如抗生腱蛋白单克隆抗体 81 C6 或 EGFR 靶向毒素偶联物 TP-38）的结果证实，创新的肿瘤靶向疗法可以改善局部控制并改善总体结果。因此，我们还将评估针对最近发现的肿瘤相关标志物的其他新型疗法，例如 EGFRvIII、糖蛋白 NMB、多药耐药蛋白 3、神经胶质瘤相关细胞表面神经节苷脂 3'-isoLM1 和 3',6'-isoLD 1、人 CMV 和脊髓灰质炎病毒受体 CD155。我们的假设是，合理设计的新颖治疗策略，要么阻断化疗耐药的关键介质，要么增强局部控制，将提高患有癌症的患者的生存率 恶性脑肿瘤，同时保持最佳生活质量。该提案的具体目标是： 具体目标 1. 开展I期和II期临床试验，评估GSTP1和PARP介导的化疗耐药抑制剂的抗肿瘤活性和安全性。具体目标 2. 进行 I 期和 II 期临床试验，以评估旨在改善局部控制的创新疗法的抗肿瘤活性和安全性，包括放射性标记的 MAb、MAb 片段、毒素缀合物、针对肿瘤相关 CMV 抗原的 DC 和溶瘤脊髓灰质炎/重组鼻病毒。具体目标 3. 确定这些治疗药物对恶性脑肿瘤患者整体生活质量的影响。