Clinical Development of 4-Hydroperoxyifosfamide

性状（由申请方提供）：4-过氧化氢异环磷酰胺（HOO-IFOS）是异环磷酰胺（IFOS）的初始代谢产物4-HO-IFOS的一种稳定、预活化形式（过氧化物）。在生理条件下，HOO-IFOS自发开环并转化为IFOS的活性细胞毒性代谢物异磷酰胺芥（IPM）。拟定研究的目的是合成足量的4-氢过氧异环磷酰胺（HOO-IFOS），以记录和验证纯度和稳定性。冻干产品将在爱荷华州大学药学服务部根据GLP/GMP指导原则制备，用于晚期癌症患者的临床使用。将验证GC/MS和HPLC测定法用于散装和药用级药物的定量。将在GLP机构使用最终产品在小鼠和犬中采用3天给药方案进行毒理学研究。将完成监测接受HOO-IFOS的犬的血浆HOO-IFOS PK和丙烯醛/氯乙醛水平的测定。在完成上述所有工作并提交给FDA后，将编制IND文件包。总之，HOO-IFOS与人胶质母细胞瘤和乳腺癌异种移植物和CPA耐药白血病小鼠模型相比具有改善的抗癌活性。SBIR申请的目标是开发一种新的前药，4-氢过氧异环磷酰胺（HOO-IFOS），其将在体内产生异磷酰胺芥子气（IPM），并减少通常在IFOS过程中产生的相关毒性-氯乙醛和丙烯醛-副产物的形成。

DESCRIPTION (provided by applicant): 4-Hydroperoxyifosfamide (HOO-IFOS) is a stable, pre-activated form (peroxide) of 4-HO-IFOS, the initial metabolite of Ifosfamide (IFOS). Under physiological conditions HOO-IFOS under goes spontaneously ring opening and conversion to isophosphoramide mustard (IPM), the active cytotoxic metabolite of IFOS. The objective of the proposed research is to synthesize 4-hydroperoxyifosfamide (HOO-IFOS) in sufficient quantity to document and validate purity and stability. A lyophilized product will be prepared at The University of Iowa, Pharmaceutical Services under GLP/GMP guidelines for clinical use in patients with advanced cancer. GC/MS and HPLC assays will be validated for quantification of bulk and pharmaceutical grade drug. Toxicology studies using a 3-day dosing regime in mice and dogs will be conducted at a GLP facility using the final product. An assay to monitor plasma HOO-IFOS PK and acrolein/chloroacetaldehyde levels in dogs receiving HOO- IFOS will be finalized. An IND package will be prepared after all the above has been finalized and submitted to the FDA. In summary - HOO-IFOS had improved anticancer activities vs. human glioblastoma and breast cancer xenografts and CPA-resistant leukemia murine models. The goal of the SBIR application will be to develop a new pro-drug, 4-hydroperoxyifosfamide (HOO-IFOS) that will generate in vivo - isophosphoramide mustard (IPM) - with reduced formation of associated toxic - chloroacetaldehyde and acrolein - by-products, normally produced during IFOS.