PHASE I STUDY OF CLORETAZINE(TM) (VNP40101M) IN CHILDREN WITH RECURRENT, PROG

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。所列机构为 中心，不一定是研究者的机构。 摘要 假设 氯瑞他嗪（VNP 40101 M），一种具有甲基化和氨甲酰化活性的DNA烷化剂，将在患有复发性、进行性或难治性原发性脑肿瘤的儿童中具有抗肿瘤活性。 具体目标 主要目的： 1.1评估氯瑞他嗪（TM）（VNP 40101 M）静脉给药（每日一次，持续5天，每6周一次）治疗复发性、进行性或难治性原发性脑肿瘤儿童的MTD并描述DLT。 次要目的： 1.2描述氯瑞他嗪（TM）（VNP 40101 M）及其活性代谢物VNP 4090 CE在复发性、进行性或难治性原发性脑肿瘤儿童中的药代动力学特征。 1.3评估暴露于氯瑞他嗪（TM）（VNP 40101 M）后儿童复发性、进行性或难治性原发性脑组织中外周血单核细胞（PBMC）中烷基鸟嘌呤烷基转移酶（AGT）的消耗。 1.4获得氯瑞他嗪（TM）（VNP 40101 M）治疗复发性、进行性或难治性原发性脑肿瘤儿童疗效的初步证据。 背景和意义 氯瑞他嗪（VNP 40101 M）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（VNP 40101 M）已经证明了针对某些选定的对目前批准的烷化剂具有抗性的肿瘤细胞系的体外和体内抗肿瘤活性。 磺酰肼前药（SHP） 双功能DNA烷化剂，包括二乙基亚硝基脲（CENUs），是用于多种癌症（包括脑肿瘤、结肠癌和淋巴瘤）的化疗药物。1 DNA交联被认为是烷化剂抗癌活性的主要途径。2，3 CENUs通过具有二乙基化、羟乙基化、氨甲酰化和乙烯基化活性的几种反应性物质引起DNA损伤。4，5. DNA交联通过鸟嘌呤残基的O-6位的初始甲基化而发生，并且是导致DNA合成停止和细胞死亡的不可逆过程。然而，DNA中嘌呤碱基的羟乙基化没有已知的有益抗肿瘤作用，但对正常细胞可能具有致突变性。4乙烯化活性没有已知的治疗益处。相反，由于异氰酸酯部分的产生而产生的氨甲酰化活性不与DNA反应，而是与包括DNA聚合酶II和烷基鸟嘌呤烷基转移酶（AGT）在内的蛋白质的巯基和胺基结合，从而抑制DNA烷基化和交联的修复。4-6可以想象，DNA修复的抑制可能增强由氯乙基化物质引起的DNA损伤的细胞毒性。因此，可能有益的是具有胆乙基化和氨基甲酸酯化活性而没有任何羟乙基化或乙烯基化性质的烷基化剂。磺酰肼类前药是一类新型的DNA烷化剂，能自发产生亲核物质，并具有选择性的甲基化和氨甲酰化活性。 氯瑞他嗪<$（VNP 40101 M）[1，2-双（甲磺酰基）-1-（2-甲基乙基）-2-（甲氨基）羰基肼] 氯瑞他嗪（VNP 40101 M）是磺酰肼前药类的第一种化合物，其已经过广泛的临床前测试，并且正在患有复发性实体恶性肿瘤（包括脑肿瘤）的成人中进行I期试验评估。 氯瑞他嗪<$（VNP 40101 M）治疗复发性脑肿瘤儿童的I期研究的依据 该药物的临床前研究已显示出对包括脑肿瘤在内的实体恶性肿瘤的广谱活性。该药物似乎比CENUs具有更好的疗效，特别是在表达AGT的肿瘤中，并且在恶性胶质瘤、成神经管细胞瘤和室管膜瘤异种移植物中表现出活性。虽然101 M单次给药在荷瘤动物中产生了延长的治愈，但在5天内分次给药的药物在相似的累积剂量下毒性较小，而不影响治愈。在复发性脑肿瘤儿童中，有必要使用分次给药方案进行该药物的I期研究，以观察DLT并在评估该患者人群的疗效之前估计MTD。起始剂量水平是根据在接受305 mg/m2每6周一次单次给药的复发性实体瘤成人I期研究中宣布的MTD的80%计算的（305 mg/m2的80%= 244 mg/m2，将在5天内给药= 45 mg/m2/天）。根据IND审查过程中FDA的建议，选择了两种可用成人MTD中较低的一种。

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. ABSTRACT HYPOTHESIS CLORETAZINE¿ (VNP40101M), a DNA alkylating agent with chlorethylating and carbomylating activities, will have anti-tumor activity in children with recurrent, progressive, or refractory primary brain tumors. SPECIFIC AIMS Primary Objective: 1.1 To estimate the MTD and describe the DLT of CLORETAZINE(TM) (VNP40101M) when administered intravenously daily for 5 days every 6 weeks to children with recurrent, progressive, or refractory primary brain tumors. Secondary Objectives: 1.2 To characterize the pharmacokinetics of CLORETAZINE(TM) (VNP40101M), and its active metabolite VNP4090CE, in children with recurrent, progressive, or refractory primary brain tumors. 1.3 To estimate depletion of alkyl guanine alkyltransferase (AGT) in peripheral blood mononuclear cells (PBMC) in children recurrent, progressive, or refractory primary brain after exposure to CLORETAZINE(TM) (VNP40101M). 1.4 To obtain preliminary evidence of efficacy of CLORETAZINE(TM) (VNP40101M) in children with recurrent, progressive, or refractory primary brain tumors. BACKGROUND AND SIGNIFICANCE CLORETAZINE¿ (VNP40101M) 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¿ (VNP40101M) has demonstrated in vitro and in vivo anti-tumor activity against certain selected tumor cell lines that are resistant to currently approved alkylating agents. Sulfonyl Hydrazine Prodrugs (SHPs) Bifunctional DNA alkylating agents including the chlorethylnitrosoureas (CENUs) are chemotherapeutic drugs used in a variety of cancers including brain tumors, colon carcinoma, and lymphomas.1 DNA cross-linking is thought to be the major pathway for anticancer activity of alkylating agents.2,3 CENUs cause DNA damage through several reactive species with chlorethylating, hydroethylating, carbomylating, and vinylating activities.4,5 DNA cross-linking occurs by initial chlorethylation of the O-6 position of guanine residues and is an irreversible process leading to cessation of DNA synthesis and cell death. However, hydroxyethylation of purine bases in DNA has no known beneficial anti-tumor effects but can be mutagenic to normal cells.4 The vinylation activity has no known therapeutic benefit. In contrast, the carbomylating activity due to generation of an isocyanate moiety, does not react with DNA but binds to thiol and amine groups of proteins including DNA polymerase II and alkylguanine alkyl transferase (AGT) and thereby inhibits repair of DNA alkylation and cross-links.4-6 It is conceivable that inhibition of DNA repair may potentiate the cytotoxicity of DNA lesions caused by the cholorethylating species. Therefore, it might be beneficial to have an alkylating agent with cholethylating and carbomylating activities without any hydroxyethylating or vinylating properties. The sulfonyl hydrazines prodrugs (SHPs) are a new class of DNA alkylating agents that spontaneously generate nucleophilic species with selective chlorethylating and carbomylating activities. CLORETAZINE¿ (VNP40101M) [1,2 -bis(methylsulfonyl)-1- (2-chlorethyl) -2- (methylamino) carbonylhydrazine] CLORETAZINE¿ (VNP40101M) is the first compound of the class of sulfonyl hydrazine pro-drugs that has undergone extensive pre-clinical testing and is being evaluated in phase I trials in adults with recurrent solid malignancies including brain tumors. Rationale for a phase I study of CLORETAZINE¿ (VNP40101M) in children with recurrent brain tumors Preclinical studies of the drug has shown broad spectrum of activity in solid malignancies including brain tumors. The drug appears to have better efficacy than CENUs especially in tumors expressing AGT and has demonstrated activity in malignant glioma, medulloblastoma, and ependymoma xenografts. While single doses of 101M have produced extended cures in animals bearing tumors, fractionated doses of the drug over 5 days was less toxic in similar cumulative dosage without compromising cure. A phase I study of this agent using a fractionated dose schedule is warranted in children with recurrent brain tumors to observe the DLTs and estimate the MTD prior to assessing efficacy in this patient population. The starting dose level is calculated based on 80% of the declared MTD in the adult phase I study in patients with recurrent solid tumors who received a dose of 305 mg/m2 given as a single dose every 6 weeks (80% of 305 mg/m2 = 244 mg/m2 which will be given over 5 days = 45 mg/m2/day). The lower of the two available adult MTDs was chosen based on recommendation of the FDA during the IND review process.