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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个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 研究中心，而研究中心不一定是研究者所在的机构。 Zometa是一种新一代高效双膦酸盐，已被批准用于治疗恶性高钙血症成人，以及与化疗联合治疗多发性骨髓瘤和实体瘤骨转移相关的骨病变。 它广泛用于具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。 双膦酸盐通过对称为破骨细胞的细胞产生毒性而改变骨环境，从而导致骨吸收减少。 Zometa是第一个影响溶骨性和成骨细胞转移性病变的双膦酸盐。 在复发性或晚期恶性肿瘤成人患者中开展的几项大型随机化研究中，与安慰剂或另一种广泛使用的双膦酸盐（称为帕米膦酸盐）相比，随机分配至Zometa的患者骨转移进展延迟，发病率（骨骼相关事件）较低。 Zometa在成人中的毒性特征可耐受，包括低钙血症、体温升高和恶心。 最值得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。 本研究的主要目的是评价Zometa联合低剂量口服环磷酰胺治疗复发性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对骨吸收标志物、细胞因子、骨相关生长因子和免疫状态的影响。 Zometa将每28天静脉给药一次。 环磷酰胺将每日口服给药，不间断（除非发生毒性）。 每个疗程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. 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. 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.