CLINICAL MONOCLONAL ANTIBODY AND MULTIMODALITY TREATMENT TRIALS

临床单克隆抗体和多模式治疗试验

• 批准号: 6273695
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 19.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273695
• 关键词: alkylating agents; antineoplastics; antitumor antibody; brain neoplasms; central nervous system neoplasms; child (0-11); clinical trials; combination cancer therapy; cyclophosphamide; dosage; drug administration routes; drug screening /evaluation; glioma; human subject; human therapy evaluation; hybrid antibody; immunoconjugates; melphalan; meningitis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; pediatric neoplasm /cancer; radiation dosage

The prognosis for most patients with primary anaplastic CNS tumor, the glioblastoma, is 8-12 months after diagnosis. The outlook is somewhat better for less common tumors, such as anaplastic astrocytoma with a 38-50% 2-year survival, but most anaplastic CNS tumors are highly resistant to currently available therapy. Occasional responses to chemotherapy are seen in recurrent tumors, but these responses are generally of short duration, and cures are rare. Median survival of patients with cancer metastatic to the brain, when untreated, is approximately four weeks from the time of diagnosis. Surgical and radiotherapeutic intervention increase survival, although the outcome is still grim with median survival less than one year. First recognized in 1870 neoplastic meningitis is now being seen with increasing frequency, no doubt reflecting more effective therapy of systemic cancer as well as heightened awareness nd improvement in diagnosis. Current therapy of leptomeningeal disease is particularly ineffective with external beam radiotherapy and intrathecal chemotherapy, specifically methotrexate, thiotepa, or cytosine arabinoside only providing modest benefits, with mean survival following leptomeningeal tumor spread measured in months. Newer therapies are needed for treatment of patients with neoplastic meningitis. The hypothesis of this proposal is that regional therapy combined with systemic therapy of primary brain tumors, metastatic brain tumors and neoplastic meningitis with radiolabeled monoclonal antibodies (MAbs) or bifunctional alkylating agents can substantially enhance therapy of these fulminant malignancies. The specific aims of this proposal are 1) to define the toxicity and activity of intrathecal radiolabelled MAb (murine and chimeric) 81C6, MAb fragment Mel-14 (murine and chimeric), and new MAbs, in the treatment of patients with neoplastic meningitis; 2) to define the toxicity and activity of intracystic radiolabelled MAb (murine and chimeric) 81C6, and new MAbs, in the treatment of patients with newly diagnosed or recurrent cystic gliomas; 3) to define the toxicity an activity of radiolabelled mAb (murine and chimeric) 81C6, MAb fragment (murine and chimeric) Mel-14, and new MAbs administered via a surgically created cystic resection cavity in the treatment of patients with newly diagnosed or recurrent primary or metastatic malignant brain tumors; 4) to define toxicity and activity of intrathecal melphalan and other alkylating agents in the treatment of patients with neoplastic meningitis; 5) to define the toxicity and activity of arterial 4-hydroperoxycyclophosphamide, melphalan, and other alkylating agents in the treatment of patients with newly diagnosied or recurrent anaplastic gliomas; 6) to define the toxicity and activity of intrathecal monoclonal antibody pseudomonas toxin conjugate B3-Lys PE38 in the treatment of patients with neoplastic meningitis; and 7) to conduct in years 3-5, Phase 2 and 3 studies combining systemic therapy reaching the entire neuraxis with the most promising regional MAb/alkylator therapy evaluated in Specific Aims 1-6.230

大多数原发性中枢神经系统肿瘤患者的预后， 胶质母细胞瘤诊断后8-12个月。 前景有些 更好的是较不常见的肿瘤，例如塑性星形胶质细胞瘤，为38-50％ 两年生存期，但大多数变性CNS肿瘤对 目前可用的治疗。 偶尔可以看到对化疗的反应 在复发性肿瘤中，但是这些反应通常持续时间很短， 治疗很少见。 癌症转移性患者的中位生存期 从未经处理的情况下，大脑从大约四个星期开始 诊断。 手术和放射治疗的干预增加了生存率， 尽管结果仍然处于严峻的状态，中位生存期不到一年。 目前在1870年首次认识到肿瘤性脑膜炎 频率增加，毫无疑问，反映了更有效的治疗 全身性癌症以及提高意识的提高 诊断。 当前的脑膜脑疾病疗法尤其是 对外束放疗和鞘内化学疗法无效， 特别是甲氨蝶呤，Thiotepa或胞嘧啶阿拉伯糖苷仅提供 适度的益处，瘦脑肿瘤扩散后平均存活率 以几个月的方式测量。 需要较新的疗法来治疗患者 肿瘤性脑膜炎。 该提议的假设是 区域疗法结合原发性脑肿瘤的全身治疗， 带有放射性标记的转移性脑肿瘤和肿瘤性脑膜炎 单克隆抗体（mAb）或双功能烷基化剂可以 大大增强了这些暴发性恶性肿瘤的治疗。 这 该提案的具体目的是1）定义毒性和活动 鞘内放射性标记的mAb（鼠和嵌合）81c6，mab碎片 MEL-14（鼠和嵌合）和新的mAb在治疗患者中 患有肿瘤性脑膜炎； 2）定义的毒性和活性 内部放射性标记的mAb（鼠和嵌合）81c6和新的mabs， 新诊断或复发性囊性神经胶质瘤患者的治疗； 3）定义放射性标记的mAb活性的毒性（鼠和 嵌合）81c6，mab碎片（鼠和嵌合）mel-14和新的mAbs 通过手术创建的囊性切除腔进行给药 治疗新诊断或经常出发的患者或 转移性恶性脑肿瘤； 4）定义毒性和活性 鞘内梅尔法兰和其他烷基化剂在治疗 肿瘤性脑膜炎的患者； 5）定义毒性和活动 动脉4-氢过氧环磷酰胺，Melphalan和其他烷基化的 治疗新诊断或经常性患者的药物 变性神经胶质瘤； 6）定义鞘内的毒性和活性 单克隆抗体假单胞菌毒素结合物B3-lys PE38 治疗肿瘤性脑膜炎的患者； 7）进行 3 - 5年，第2阶段和第3阶段的研究结合了全身治疗 整个神经术，最有前途的区域mAB/烷基疗法 在特定目标1-6.230中进行了评估