Phase 2 Study of Poly-ICLC in the Treatment of Pediatric Low Grade Gliomas

描述（由申请人提供）： 脑肿瘤是儿童时期最常见的实体瘤，因此在美国儿童死亡率很高。低级别星形细胞瘤和神经胶质瘤（LGG）是最常见的儿童脑肿瘤类型（占儿童脑肿瘤的36%）。根据2009年发布的监测、流行病学和最终结果（SEER）数据库的数据，估计美国儿科人群中LGG的发病率为每年4，600例。在LGG的治疗中避免或延迟放射治疗，以防止神经认知能力下降，并防止转化为恶性程度更高的肿瘤（III级和IV级）。在该提议中，假设LGG更可能对聚ICLC（一种TLR 3激动剂）产生应答，并且肿瘤和间质隔室中TLR 3的信号传导途径的表征将预测对该疗法的应答。这是一项开放标签、多机构、II期临床试验，采用20 mcg/kg体重/剂量的聚ICLC每周两次肌内（IM）给药，以确定聚ICLC治疗复发性或进行性LGG儿童的放射学缓解率。治疗的总时长为2年，每个周期为28天。这三个具体目标是：1）确定聚-ICLC在治疗儿科复发性LGG中是否具有抗肿瘤活性，2）确定该药剂在LGG群组中的毒性并评价用聚-ICLC治疗的患者的QOL终点，和3）进行外周血单核细胞（PBMC）的广泛分子谱分析，在用聚ICLC治疗之前和之后的患者样品中的血清和脑脊液，以努力鉴定将预测对该疗法的响应性的生物标志物特征。

DESCRIPTION (provided by applicant): Brain tumors are the most common solid tumor diagnosed in childhood and thus account for significant childhood mortality in the United States. Low-grade astrocytomas and gliomas (LGG) are the most common type of brain tumor of childhood (36% of childhood brain tumors). Based on data from the Surveillance, Epidemiology, and End Results (SEER) database published in 2009, it is estimated that the incidence of LGG in the pediatric population is 4,600 cases diagnosed annually in the US. Radiotherapy is avoided or delayed in the treatment of LGG to prevent neurocognitive decline and to prevent transformation to a more malignant grade of tumor (grade III and IV). In this proposal, it is hypothesized that LGG are more likely to respond to poly-ICLC (a TLR3 agonist) and that characterization of signaling pathways for TLR3 in the tumor and stromal compartment will predict response to this therapy. This is an open label, multi-institutional, phase 2 clinical trial of poly-ICLC with dosing of 20 mcg/kg body weight/dose administered intramuscularly (IM) twice weekly to determine the radiographic response rate to poly-ICLC in the treatment of children with recurrent or progressive LGG. Total length of therapy will be two years with each cycle being 28 days in length. The three specific aims are to: 1) determine if poly-ICLC has antitumor activity in the treatment of pediatric recurrent LGG, 2) determine the toxicity of this agent in a LGG cohort and to evaluate a QOL endpoint in patients treated with poly-ICLC, and 3) perform extensive molecular profiling of peripheral blood mononuclear cells (PBMCs), serum and cerebral spinal fluid in patients samples before and after treatment with poly-ICLC in an effort to identify a biomarker signature that will predict responsiveness to this therapy.