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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。唑来膦酸（Zometa¿¿）由nci赞助的14家儿童医院组成的联盟，专门治疗患有神经母细胞瘤的儿童。佐美达（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，以及多发性骨髓瘤和实体瘤骨转移相关骨病变联合化疗的管理。广泛用于有骨转移潜力的成人恶性肿瘤，如乳腺癌、多发性骨髓瘤和前列腺癌。双膦酸盐通过对破骨细胞产生毒性从而减少骨吸收从而改变骨环境。佐美达是第一个影响溶骨和成骨细胞转移性病变的双膦酸盐。在几项针对复发或晚期恶性肿瘤的成人的大型随机研究中，与安慰剂或另一种广泛使用的双膦酸盐帕米膦酸盐相比，随机接受佐美达治疗的患者骨转移进展延迟，发病率（骨骼相关事件）更低。佐美达在成人中的毒性是可耐受的，包括低钙血症、体温升高和恶心。最令人担忧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，双膦酸盐延缓了移植到免疫功能受损小鼠的神经母细胞瘤的溶骨性病变的进展，而佐美达与低剂量环磷酰胺的联合使用似乎延长了总生存期。本研究的主要目的是评估佐美达联合低剂量口服环磷酰胺治疗复发或难治性神经母细胞瘤儿童的最大耐受剂量。可选研究将评估佐美达在神经母细胞瘤儿童中的药代动力学，并检查佐美达对骨吸收标志物、细胞因子、骨相关生长因子和免疫状态的影响。佐美达将每28天静脉注射一次。环磷酰胺将每天口服给药，不间断（除非出现毒性）。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.