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

这个子项目是众多研究子项目之一

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.