PBTC-017: PHASE I STUDY OF CLORETAZINE (VNP40101M) IN CHILDREN WITH RECURRENT,

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究的具体目的是评估氯瑞他嗪？（VNP 40101 M）的最大耐受剂量（MTD），并描述其剂量限制毒性（DLT），该药物在患有复发性、进行性或难治性原发性脑肿瘤的儿童和年轻人中每6周静脉给药5天。 氯瑞他嗪是一种新型烷化剂，在小鼠肿瘤模型中具有广谱抗肿瘤活性。它被认为是专门攻击鸟嘌呤的O 6位置，形成G-C DNA交联。氯瑞他嗪已经证明了对某些选定的肿瘤细胞系的体外和体内抗肿瘤活性，所述肿瘤细胞系对目前批准的烷化剂具有抗性。 氯瑞他嗪将在30分钟内静脉给药，连续5天，每6周一次。连续6周为1个疗程。将尽一切努力避免在每个疗程期间中断治疗，特别是在DLT评估阶段。第一个疗程应在不超过7天内完成。在任何疗程中，允许患者跳过不超过一天的治疗。在任何疗程中，可以在开始治疗后7天内补齐漏服的药物剂量。剂量是基于每个疗程开始时计算的体表面积。在登记前2周内评估了充分的肺和心脏功能。 根据PBTC-012中的经验估计终点，PBTC-012显示平均每月增加约2例患者。为了研究7个剂量水平，计划将12例患者置于MTD，预计每个分层最多需要30例患者，考虑到研究将关闭入组的时间，这将需要在1年至18个月内进行患者入组。

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. The specific aim of this study is to estimate the Maximum tolerated dose (MTD) and describe the Dose Limiting Toxicities (DLT) of CLORETAZINE¿ (VNP40101M) when administered intravenously daily for five days every six weeks to children and young adults with recurrent, progressive or refractory primary brain tumors. CLORETAZINE¿ is a novel alkylating agent with a broad spectrum of anti-tumor activity in murine tumor models. It is believed to specifically attack the O6 position of guanine, forming G-C DNA cross-links. CLORETAZINE¿ has demonstrated in vitro and in vivo anti-tumor activity against certain selected tumor cell lines that are resistant to currently approved alkylating agents. CLORETAZINE¿ will be given intravenously over 30 minutes for 5 consecutive days every 6 weeks. Six consecutive weeks will constitute one course of treatment. Every attempt will be made to avoid interruption of treatment during each course particularly during the DLT assessment phase. The first course of treatment should be completed in not more than 7 days. Patients are allowed to skip no more than one day of treatment during any course. This missed dose of drug can be made up within 7 days of starting treatment during any course. Dosing is based on the body surface area calculated at the beginning of each course of therapy. Adequate pulmonary and cardiac function assessed within 2 weeks prior to registration. Endpoints are estimated based on experience in PBTC-012 which showed that the average monthly accrual is about two patients. To investigate the seven dose levels with the plan to put 12 patients at the MTD, a maximum of 30 patients per stratum are expected to be needed, which will require patient accrual over a year to 18 months considering the times the study will be closed to accrual.