Phase II Study of 44Gy from 131I-81C6 for CNS Tumors

描述(由申请人提供)：多形性胶质母细胞瘤是最常见的原发恶性脑肿瘤，其患者的预后仍然令人沮丧。目前包括手术、放疗和化疗在内的治疗方法的中位生存期距离确诊还有40-50周，而现有的抢救疗法在复发后无效。大多数病例在原发部位进展，这表明地方控制是改善结果的关键第一步。为了应对恶性脑肿瘤患者对有效、创新疗法的迫切需求，我们中心开发了专门针对肿瘤抗原的放射性标记单抗(MAb)。81C6，小鼠IgG2b单抗与恶性胶质瘤高度上调和表达的细胞外基质蛋白Tenascin的异构体反应。之前完成的I期和II期研究中，将固定剂量的131I标记的81C6直接注入外科手术创建的切除腔(SCRC)，证实了这种方法以可接受的毒性提高了恶性胶质瘤患者的存活率。伴随这些试验进行的剂量学研究的一个关键观察结果是，结果与SCRC周界的剂量关系最为密切。具体地说，接受SCRC周边低于44Gy射线照射的患者，放射性坏死的毒性最小，但肿瘤复发率较高。相反，那些接受超过44GY的患者肿瘤复发率较低，但有症状的放射性坏死率较高。我们的假设是，我们的II期研究使用131I-81C6，将44Gy射线照射到2厘米的SCRC周长，将提高新诊断的恶性胶质瘤患者的存活率，同时将对正常中枢神经组织的辐射损伤降至最低。本方案的具体目的是：1.明确131I标记的抗Tenascin单抗81C6对新诊断的恶性脑胶质瘤患者切除腔周长2 cm处分次给予44GyTenascin的疗效；2.进一步确定该方法的毒性和3.确定该治疗方法对生活质量的影响。

DESCRIPTION (provided by applicant): The outcome for patients with glioblastoma multiforme, the most common primary malignant brain tumor, remains dismal. Median survival with current therapy including surgery, radiotherapy and chemotherapy remains 40-50 weeks from diagnosis while available salvage therapies are ineffective following recurrence. Most cases progress at the primary site indicating that local control is the critical first step to improve outcome. In response to the dire need for effective, innovative therapies for patients with malignant brain tumors, our center has developed radiolabeled monoclonal antibodies (mAB) that specifically target tumor antigens. 81C6, a murine IgG2b mAB reacts with an isoform of the extracellular matrix protein tenascin which is highly upregulated and expressed by malignant glioma. Previously completed phase I and II studies in which a fixed dose of 131I-labeled 81C6 was administered directly into the surgical created resection cavity (SCRC), confirmed that this approach improves survival for patients with malignant glioma with acceptable toxicity. A key observation from dosimetry studies accompanying these trials is the demonstration that outcome correlated most closely with delivered dose to the SCRC perimeter. Specifically, patients who received less than 44 Gy to the SCRC perimeter had minimal toxicity from radionecrosis but had a higher rate of tumor recurrence. Conversely those patients who received more than 44 Gy had a lower rate of tumor recurrence but a higher rate of symptomatic radionecrosis. Our HYPOTHESIS is that our phase II study with 131I -81C6 administered to deliver 44 Gy to the 2 cm SCRC perimeter will improve survival of patients with newly diagnosed malignant glioma while minimizing radiation injury to normal CNS tissue. The SPECIFIC AIMS of this proposal are: Specific Aim 1. To define the efficacy of 131I -labeled anti-tenascin monoclonal antibody 81C6 administered at a dose to deliver 44 Gy to the 2 cm perimeter of resection cavity of patients with newly diagnosed malignant glioma; Specific Aim 2. To further define the toxicity of this approach and Specific Aim 3.To determine the impact of this therapy on quality of life.