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

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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.