NANT 2004-01: A PHASE I STUDY OF ZOLEDRONIC ACID (ZOMETA) WITH CYCLOPHOSPHAMIDE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。NANT是由14家儿童医院组成的专门治疗神经母细胞瘤的儿童医院联盟，由NANT开发的唑来膦酸。Zometa是新一代高效双膦酸盐，已被批准用于治疗成人恶性肿瘤高钙血症，并结合化疗治疗与多发性骨髓瘤相关的骨病变和实体瘤的骨转移。它被广泛用于乳腺癌、多发性骨髓瘤和前列腺癌等具有骨转移潜能的成人恶性肿瘤。双膦酸盐通过对称为破骨细胞的细胞产生毒性，从而改变骨环境，从而减少骨吸收。Zometa是第一个同时影响溶骨性和成骨转移性病变的双膦酸盐。在对患有复发或晚期恶性肿瘤的成年人进行的几项大型随机研究中，与安慰剂或另一种广泛使用的双膦酸帕米膦酸盐相比，随机服用Zometa的患者骨转移进展延迟，发病率(骨骼相关事件)较少。佐美他在成人中的毒性特征是可以耐受的，包括低钙血症、体温升高和恶心。最受关注的毒性是肾功能下降，这似乎与累积剂量和给药剂量率有关。在临床前研究中，双膦酸盐延缓了神经母细胞瘤移植到免疫缺陷小鼠体内的溶骨性病变的进展，而卓美他和低剂量环磷酰胺的联合应用似乎延长了总体生存时间。本研究的主要目的是评价佐美他联合小剂量环磷酰胺治疗儿童复发性或难治性神经母细胞瘤的最大耐受量。可选研究将评估Zometa在神经母细胞瘤儿童中的药代动力学，并检查Zometa对骨吸收标记物、细胞因子、骨相关生长因子和免疫状态的影响。佐美他将每28天静脉注射一次。环磷酰胺每日口服，不间断给药(除非毒性加重)。每个疗程为28天。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Zoledronic Acid (Zometa¿¿) by NANT, a NCI-sponsored consortium of 14 Children's Hospitals that specialize in treating children with neuroblastoma. Zometa is a new generation, highly potent bisphosphonate that has been approved for treatment of adults with hypercalcemia of malignancy, and management of bone lesions associated with multiple myeloma and bone metastases from solid tumors in combination with chemotherapy. It is widely used in adult malignancies with potential for bone metastasis such as breast cancer, multiple myeloma and prostate cancer. Bisphosphonates change the bone environment by causing toxicity to cells called osteoclasts resulting in decreased bone resorption. Zometa is the first bisphosphonate to affect both osteolytic and osteoblastic metastatic lesions. In several large randomized studies in adults with recurrent or advanced malignancies, patients randomized to Zometa had delay in progression of bone metastases and less morbidity (skeletal related events) when compared to either placebo or another widely used bisphosphonate called pamidronate. The toxicity profile of Zometa in adults has been tolerable and includes hypocalcemia, temperature rise, and nausea. The most concerning toxicity is decline in renal function that appears to be related to cumulative dose and the dose rate of administration. In pre-clinical studies bisphosphonates delayed progression of osteolytic lesions in neuroblastoma tumors xenografted into immunocompromised mice while the combination of Zometa with low dose cyclophosphamide appeared to prolong overall survival. The primary aim of this study is to evaluate the maximum tolerated dose of Zometa combined with low dose oral cyclophosphamide in children with recurrent or refractory neuroblastoma. Optional studies will evaluate the pharmacokinetics of Zometa in children with neuroblastoma and examine the effect of Zometa on markers of bone resorption, cytokines, bone-related growth factors and immune status. Zometa will be administered intravenously every 28 days. Cyclophosphamide will be administered daily as an oral dose without interruption (unless toxicity supervenes). Each course of therapy will be 28 days.