CLINICAL MONOCLONAL ANTIBODY AND MULTIMODALITY TREATMENT TRIALS

大多数原发间变性中枢神经系统肿瘤患者的预后 胶质母细胞瘤，确诊后8-12个月。前景有些不乐观 更适用于不常见的肿瘤，如间变性星形细胞瘤，其发病率为38-50% 生存2年，但大多数间变性中枢神经系统肿瘤对 目前可用的治疗方法。偶尔对化疗有反应 在复发肿瘤中，但这些反应通常持续时间较短， 而且治愈的方法很少。转移性癌症患者的中位生存期 大脑，在未经治疗的情况下，大约在四周后 诊断。外科手术和放射治疗干预可提高存活率， 尽管结果仍然严峻，中位生存期不到一年。 1870年首次被发现的肿瘤性脑膜炎现在被认为是 频率的增加，无疑反映了更有效的治疗 系统性癌症以及提高认识和改善 诊断。目前对软脑膜疾病的治疗尤其是 外照射和鞘内化疗无效， 具体地说，甲氨蝶呤、硫代替巴或阿糖胞苷仅提供 软脑膜肿瘤扩散后的平均生存期为适度的益处 以月为单位。需要更新的疗法来治疗病人 患有肿瘤性脑膜炎。这项提议的假设是 局部治疗结合全身治疗原发脑肿瘤， 放射性标记转移性脑瘤和肿瘤性脑膜炎 单抗(MAb)或双官能性烷基化试剂 大大加强对这些暴发性恶性肿瘤的治疗。这个 这项提案的具体目的是1)确定其毒性和活性 鞘内放射性标记单抗(鼠源和嵌合体)81C6，单抗片段 MEL-14(小鼠和嵌合体)和新的单抗在患者治疗中的应用 肿瘤性脑膜炎；2)确定其毒性和活性 囊内放射性标记单抗(鼠源和嵌合体)81C6和新的单抗，在 初诊或复发性囊性胶质瘤患者的治疗； 3)确定放射性标记单抗(小鼠和小鼠)的毒性和活性 嵌合体)81C6、单抗片段(鼠源和嵌合体)MEL-14和新的单抗 通过外科手术创建的囊性切除腔给药 初诊或复发的原发或复发患者的治疗 转移性恶性脑瘤；4)确定其毒性和活性 鞘内注射马法兰及其他烷化剂治疗腰椎管狭窄症 肿瘤性脑膜炎患者；5)确定毒性和活性 动脉4-羟基过氧环磷酰胺、马法兰和其他烷基化 治疗初诊或复发患者的药物 间变性胶质瘤：6)确定鞘内注射的毒性和活性 单抗假单胞菌毒素结合物B3-Lys PE38在小鼠体内的应用 治疗肿瘤性脑膜炎患者；以及7)在 3-5年，2期和3期研究结合系统治疗达到 最有前景的局部单抗/烷化剂治疗的整个神经轴 在具体目标1-6.230中进行评估

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