Saulnier Sholler Giselle L, Bergendahl Genevieve M, Brard Laurent, Singh Ajay P, Heath Barry W, Bingham Peter M, Ashikaga Taka, Kamen Barton A, Homans Alan C, Slavik Marni A, Lenox Shannon R, Higgins Timothy J, Ferguson William S
Department of Pediatrics, Vermont Children's Hospital, Burlington, VT, USA.
J Pediatr Hematol Oncol. 2011 Jan;33(1):25-30. doi: 10.1097/MPH.0b013e3181f47061.
The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.
这项1期研究的主要目的是确定最大耐受剂量（MTD），并评估硝呋替莫单药以及与环磷酰胺和拓扑替康联合用药在多名复发/难治性小儿神经母细胞瘤患者中的安全性。次要目的是评估硝呋替莫的药代动力学和治疗反应。为此，我们进行了一项口服硝呋替莫每日剂量递增试验，并进行毒性监测以确定MTD，随后进行3个周期的硝呋替莫与环磷酰胺和拓扑替康联合用药。采集样本以确定药代动力学参数，即最大浓度、达到最大浓度的时间以及0至8小时的曲线下面积。通过影像学和放射性核素（I-间碘苄胍）成像、尿儿茶酚胺测量以及骨髓疾病清除情况来评估治疗反应。我们确定硝呋替莫的MTD为30mg/kg/天。非剂量限制性毒性主要为恶心和神经病变。2名患者在40mg/kg/天剂量时的剂量限制性毒性分别为3级肺出血和3级神经病变（可逆）。总体而言，小儿患者对30mg/kg/天剂量的硝呋替莫耐受性良好，硝呋替莫单药及与化疗联合用药均可见肿瘤反应。目前正在进行一项2期研究以确定硝呋替莫的抗肿瘤疗效。
