CLINICAL MONOCLONAL ANTIBODY AND MULTIMODALITY TREATMENT TRIALS

大多数原发性间变性CNS肿瘤患者的预后， 胶质母细胞瘤是诊断后8-12个月。 前景有点 对于不常见的肿瘤更好，如间变性星形细胞瘤，38-50% 2-年生存率，但大多数间变性CNS肿瘤对 目前可用的疗法。 偶尔可见化疗反应 在复发性肿瘤中，但这些反应通常持续时间短， 治愈方法很少见 癌症转移至 大脑，当未经治疗时，大约四周后， 诊断. 手术和放射治疗可以提高生存率， 尽管结果仍然很严峻，中位生存期不到一年。 肿瘤性脑膜炎于1870年首次被发现， 增加频率，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. 目前软脑膜疾病的治疗特别是 外照射放疗和鞘内化疗无效， 特别是甲氨蝶呤、噻替派或阿糖胞苷， 温和的获益，软脑膜肿瘤扩散后的平均生存期 以月计算。 需要新的治疗方法来治疗患者 肿瘤性脑膜炎 这一提议的假设是， 原发性脑肿瘤的局部治疗与全身治疗相结合， 转移性脑肿瘤和肿瘤性脑膜炎的放射性标记 单克隆抗体（MAb）或双功能烷化剂可 显著增强了对这些暴发性恶性肿瘤治疗。 的 该提案的具体目标是：1）确定毒性和活性 鞘内放射性标记MAb（鼠和嵌合）81 C6，MAb片段 Mel-14（鼠和嵌合）和新的单克隆抗体在患者治疗中的应用 肿瘤性脑膜炎; 2）确定毒性和活性 囊内放射性标记单克隆抗体（鼠和嵌合）81 C6和新单克隆抗体， 新诊断或复发的囊性胶质瘤患者的治疗; 3)为了确定放射性标记的mAb（鼠和鼠）的毒性和活性， 嵌合）81 C6、MAb片段（鼠和嵌合）Mel-14和新MAb 通过外科手术创建的囊性切除腔， 治疗新诊断或复发的原发性或 转移性恶性脑肿瘤; 4）确定 鞘内美法仑和其他烷化剂治疗 肿瘤性脑膜炎患者; 5）确定毒性和活性 动脉4-氢过氧环磷酰胺，美法仑，和其他烷化剂 治疗新诊断或复发的 间变性胶质瘤; 6）确定鞘内注射的毒性和活性 单克隆抗体假单胞菌毒素结合物B3-Lys PE 38 治疗肿瘤性脑膜炎患者;以及7）在 3-5年，II期和III期研究结合全身治疗， 最有希望的局部MAb/烷化剂治疗 在具体目标1-6.230中评价

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