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

氯雷他嗪 (TM) (VNP40101M) 在复发性、进展性儿童中的 I 期研究

• 批准号: 7605886
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605886
• 关键词: Adult; Alkylating Agents; Amines; Animals; Brain; Brain Neoplasms; Cell Death; Child; Class; Colon Carcinoma; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Alkylation; DNA Binding; DNA Damage; DNA Polymerase II; DNA Repair Inhibition; DNA biosynthesis; DNA chemical synthesis; DNA lesion; Daily; Dose; Drug Kinetics; Drug usage; Ependymoma; Exposure to; Funding; Generations; Grant; Guanine; Hydrazine; Hydrazines; In Vitro; Institution; Isocyanates; Lymphoma; Malignant Glioma; Malignant Neoplasms; Modeling; Mus; Normal Cell; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Population; Positioning Attribute; Process; Prodrugs; Property; Proteins; Purines; Recommendation; Recurrence; Refractory; Research; Research Personnel; Resistance; Resources; Schedule; Solid; Solid Neoplasm; Source; Sulfhydryl Compounds; Testing; Therapeutic; Thinking; Transferase; Tumor Cell Line; United States Food and Drug Administration; United States National Institutes of Health; VNP40101M; Week; Xenograft procedure; abstracting; alkyltransferase; anticancer activity; base; crosslink; cytotoxicity; day; dosage; in vivo; medulloblastoma; novel; pre-clinical; preclinical study; purine; repaired; tumor

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 抽象的 假设 Cloretazine (VNP40101M) 是一种具有氯乙基化和羧甲酰化活性的 DNA 烷化剂，对患有复发性、进行性或难治性原发性脑肿瘤的儿童具有抗肿瘤活性。 具体目标 主要目标： 1.1 评估患有复发性、进行性或难治性原发性脑肿瘤的儿童每 6 周 5 天每天静脉注射氯雷他嗪 (VNP40101M) 的 MTD 并描述 DLT。 次要目标： 1.2 表征氯雷他嗪 (VNP40101M) 及其活性代谢物 VNP4090CE 在患有复发性、进行性或难治性原发性脑肿瘤的儿童中的药代动力学。 1.3 评估暴露于CLORETAZINE(TM) (VNP40101M)后复发性、进行性或难治性原发性脑部儿童的外周血单核细胞(PBMC)中烷基鸟嘌呤烷基转移酶(AGT)的消耗。 1.4 获得CLORETAZINE(TM) (VNP40101M)对患有复发性、进行性或难治性原发性脑肿瘤的儿童的疗效的初步证据。 一、背景及意义 Cloretazine¿ (VNP40101M) 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。据信它会特异性攻击鸟嘌呤的 O6 位，形成 G-C DNA 交联。 Cloretazine (VNP40101M) 已在体外和体内证明对某些对目前批准的烷化剂耐药的选定肿瘤细胞系具有抗肿瘤活性。 磺酰肼前药 (SHP) 包括氯乙基亚硝基脲 (CENU) 在内的双功能 DNA 烷化剂是用于治疗多种癌症（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 CENU 通过几种具有氯乙基化、 氢乙基化、羧基化和乙烯基化活性。4,5 DNA 交联是通过鸟嘌呤残基 O-6 位的初始氯乙基化发生的，是一个不可逆过程，导致 DNA 合成停止和细胞死亡。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，但可能对正常细胞产生诱变作用。4乙烯基化活性没有已知的治疗益处。相反，由于异氰酸酯部分的生成而产生的羧基化活性不与 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 修复的抑制可能会增强 DNA 的细胞毒性。 由氯乙基化物种引起的损伤。因此，拥有具有胆乙基化和羧甲酰化活性而没有任何羟乙基化或乙烯基化性质的烷化剂可能是有益的。磺酰肼前药 (SHP) 是一类新型 DNA 烷化剂，可自发产生具有选择性氯乙基化和羧甲酰化活性的亲核物质。 氯雷嗪¿ (VNP40101M) [1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨基)羰基肼] Cloretazine¿ (VNP40101M) 是磺酰肼前药类别中的第一种化合物，经过了广泛的临床前测试，并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。 氯雷他嗪 (VNP40101M) 在患有复发性脑肿瘤的儿童中进行 I 期研究的基本原理 该药物的临床前研究表明，它对包括脑肿瘤在内的实体恶性肿瘤具有广泛的活性。该药物似乎比 CENU 具有更好的疗效，尤其是在表达 AGT 的肿瘤中，并且已在恶性神经胶质瘤、髓母细胞瘤和室管膜瘤异种移植物中显示出活性。虽然单剂量的 101M 对患有肿瘤的动物产生了延长的治愈效果，但在 5 天内分次剂量的药物在相似的累积剂量下毒性较小，且不影响治愈。在患有复发性脑肿瘤的儿童中，有必要使用分次剂量方案对该药物进行 I 期研究，以观察 DLT 并估计 MTD，然后再评估该患者群体的疗效。起始剂量水平是根据成人 I 期研究中公布的 MTD 的 80% 计算的，受试者为复发性实体瘤患者，每 6 周接受一次 305 mg/m2 剂量（305 mg/m2 的 80% = 244 mg/m2，将在 5 天内给药 = 45 mg/m2/天）。根据 FDA 在 IND 审查过程中的建议，选择了两个可用的成人 MTD 中较低的一个。