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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要 假设 ClORETAZINE(VNP40101M)是一种具有氯乙基化和碳甲基化活性的DNA烷化剂，将对复发、进展性或难治性原发脑肿瘤的儿童具有抗肿瘤活性。 具体目标 主要目标： 1.1对患有复发、进展性或难治性原发脑肿瘤的儿童，每6周每日静脉注射5天，以评估CLORETAZINE(TM)(VNP40101M)的MTD和DLT。 次要目标： 1.2研究CLORETAZINE(TM)(VNP40101M)及其活性代谢物VNP4090CE在儿童复发性、进展性或难治性原发脑肿瘤中的药代动力学。 1.3评估暴露于CLORETAZINE(TM)(VNP40101M)后，儿童复发性、进展性或难治性原发脑中外周血单个核细胞(PBMC)中烷基鸟嘌呤烷基转移酶(AGT)的耗竭情况。 1.4获得CLORETAZINE(TM)(VNP40101M)治疗儿童复发性、进展性或难治性原发脑肿瘤疗效的初步证据。 背景和意义 CLORETAZINE(VNP40101M)是一种在小鼠肿瘤模型中具有广谱抗肿瘤活性的新型烷化剂。它被认为是特异性地攻击鸟嘌呤的O6位，形成G-C DNA交联链。CLORETAZINE(VNP40101M)已经在体外和体内证明了对某些选定的肿瘤细胞株的抗肿瘤活性，这些肿瘤细胞株对目前批准的烷基化药物具有耐药性。 磺酰肼类前药(SHPS) 包括氯乙基亚硝脲(Cenus)在内的双功能DNA烷基化试剂是用于包括脑瘤、结肠癌和淋巴瘤在内的各种癌症的化疗药物。1 DNA交联剂被认为是烷基化剂抗癌活性的主要途径。2，3cenus通过几个具有氯乙基化、氢乙基化、甲基化和乙烯基化活性的活性物种引起DNA损伤。4，5DNA交联剂通过鸟嘌呤残基O-6位的初始氯乙基化发生，是一个导致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的抗肿瘤作用，但可以对正常细胞产生突变。4乙烯化活性没有已知的治疗益处。相反，由于产生异氰酸酯部分而产生的羧化活性不与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)在内的蛋白质的硫醇和氨基结合，从而抑制DNA烷基化和交联键的修复。4-6可以想象，抑制DNA修复可能会增强由胆碱甲基化物种造成的DNA损伤的细胞毒性。因此，拥有一种具有胆乙基化和羧基化活性而不具有任何羟乙基化或乙烯基化性质的烷化剂可能是有益的。磺酰肼类前药(SHPS)是一类新型的DNA烷基化试剂，能自发产生具有选择性氯乙基化和羧基化活性的亲核物种。 1，2-二(甲磺酰基)-1-(2-氯乙基)-2-(甲氨基)甲酰肼 CLORETAZINE(VNP40101M)是磺酰肼类前体药物中的第一种化合物，已经过广泛的临床前测试，目前正在对患有包括脑瘤在内的复发性实体恶性肿瘤的成年人进行I期试验评估。 氯雷他嗪(VNP40101M)治疗儿童复发性脑肿瘤I期研究的理论基础 对该药物的临床前研究表明，该药物在包括脑瘤在内的实体恶性肿瘤中具有广泛的活性。该药似乎比CENUS有更好的疗效，特别是在表达AGT的肿瘤中，并在恶性胶质瘤、髓母细胞瘤和室管膜瘤异种移植中显示出活性。虽然单次剂量的101M在携带肿瘤的动物身上产生了延长的治愈时间，但在类似累积剂量的情况下，在不影响治愈的情况下，分次剂量超过5天的毒性较小。对于复发性脑肿瘤的儿童，在评估疗效之前，有必要对这种药物进行I期分次剂量计划研究，以观察DLTS并估计MTD。起始剂量水平是以成人I期研究中宣布的MTD的80%为基础计算的，这些患者每6周接受一次剂量305 mg/m2(305 mg/m2的80%=244 mg/m2，将在5天以上给予=45 mg/m2/天)。两种可用的成人MTDS中较低的一种是在IND审查过程中根据FDA的建议选择的。

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.