4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) Phase I Clinical Tr

描述（由申请人提供）：拟议研究的目的是在晚期癌症患者中进行4-去甲基-胆固醇氧羰基彭洛美定（DM-PEN）的碳酸盐衍生物4-去甲基-彭洛美定（DM-PEN）的1期临床试验。后者是彭洛美定（PEN）的抗肿瘤活性、无神经毒性代谢物。PEN在临床试验中表现活跃，但具有明显的神经毒性，因此该试验被取消。dm - chocc - pen是一种可以穿过血脑屏障且无毒的衍生物。在小鼠脑内（IC）植入胶质瘤和乳腺癌异种移植模型中，dm - chocc - pen产生了长期生存（无体重减轻）的完全缓解。相比之下，DM-PEN在IC模型中没有产生完全响应。dm - chocc - pen已完成临床前/毒理学/配方研究，正在生产中，并将准备进行临床研究。该产品将通过单一剂量表给药。dm - chocc - pen在体外对人类乳腺癌外植体和胶质瘤细胞也有活性，这支持了它不需要事先激活的概念。该产品将作为乳剂使用，该配方在冰箱储存条件下已稳定50 - 20年。该包装已通过FDA审查- IND 68,876。这项I期研究的具体目标是：1)对dm - chocc - pen在晚期癌症患者中的I期评估，以确定最大耐受剂量（MTD）并表征相关的主要毒性。2)在I期临床试验中研究dm - chocc - pen的药代动力学和药效学特征。3)评估抗肿瘤活性，并以电子方式存储/分析数据。公共卫生相关性：dm - chocc -PEN是PEN的新型碳酸胆固醇衍生物，由DEKK-TEC设计并在南方研究所进行筛选。在颅内植入的U251和D54胶质瘤和MX-1乳腺癌异种移植模型中，它已显示出令人印象深刻的能力，可以穿过血脑屏障并产生CR和LTS。随后，DEKK-TEC完成了临床前研究，开发了配方验证，准备了IND，产品已准备好进行1期临床试验。该产品将于2007年秋季制成乳剂用于临床。该项目已通过FDA -IND 68,876审查。

DESCRIPTION (provided by applicant): The object of the proposed research is to conduct a Phase 1 clinical trial with 4-demethyl-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), a carbonate derivative of 4-demethyl-penclomedine (DM-PEN) in patients with advanced cancer. The latter is the antitumor active, non-neurotoxic metabolite of penclomedine (PEN). PEN was active in clinical trials but possessed significant neurotoxicity and the trial was cancelled. DM-CHOC-PEN was synthesized as a derivative that could cross the blood brain barrier and not be toxic. DM-CHOC-PEN produced complete remissions with long term survival (and no weight loss) vs. intracerebrally (IC) implanted gliomas and breast cancer xenograft models in mice. In contrast DM-PEN did not produce complete responses in the IC models. DM-CHOC-PEN has completed pre-clinical/toxicology/formulation studies, is being manufactured and will be ready for clinical studies. The product will be administered via a single dose schedule. DM-CHOC-PEN is also active in vitro vs. human breast cancer explants and glioma cells, supporting the concept that it does not require prior activation. The product will be administered as an emulsion, the formulation has been stable for > 2 year at refrigerator storage conditions. The package has been reviewed by the FDA - IND 68,876. The specific objectives of this Phase I study will be to: 1) Conduct a Phase 1 evaluation of DM-CHOC-PEN in patients with advanced cancer to determine the maximum tolerated dose (MTD) and characterize the related principal toxicities. 2) Study the pharmacokinetic and pharmacodynamic profiles of DM-CHOC-PEN in the Phase I clinical trial. 3) Evaluate antitumor activity and electronically store/analyze data. PUBLIC HEALTH RELEVANCE: DM-CHOC-PEN is a novel cholesteryl carbonate derivative of PEN that was designed at DEKK-TEC and screened at Southern Research Institute. It has demonstrated impressive abilities to cross the BBB and produce CR and LTS in intracranially implanted U251 and D54 gliomas and MX-1 breast cancer xenograft models. Subsequently, DEKK-TEC has completed the pre-clinical studies, developed a formulation -validated, prepared the IND and the product is ready for a Phase 1 clinical trial. The product will be ready in the Fall '07 for clinical use as an emulsion. The project has been reviewed by the FDA -IND 68,876.