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

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) I期临床试验

基本信息

批准号：
7481597
负责人：
Lee ROY MORGAN
金额：
$ 14.1万
依托单位：
DEKK-TEC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481597
关键词：
Accounting Adult Advanced Malignant Neoplasm Animals Autopsy Back Blood - brain barrier anatomy Blood Circulation Body Weight decreased Brain Brain Neoplasms Breast Cancer Etiology Cancer cell line Canis familiaris Carbonates Cause of Death Cessation of life Child Childhood Clinical Clinical Research Clinical Trials Condition Data Analyses Diagnosis Diffuse Disease remission Dose Drug Formulations Drug Kinetics Emulsions Evaluation Glioma Hepatic Human Implant In Vitro In complete remission Liver Long-Term Survivors Lung MX-1 Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Maximum Tolerated Dose Medical Modeling Monitor Mus Neoplasm Metastasis Neuraxis Operative Surgical Procedures Pathology Patients Penetration Pharmacodynamics Phase Phase I Clinical Trials Pontine structure Process Property Public Health Refrigeration Research Research Institute Research Project Grants Rodent Schedule Supporting Cell Temperature Tissues Toxic effect Toxicology U251 United States Food and Drug Administration Xenograft Model analog anticancer activity concept design falls improved irritation liver function malignant breast neoplasm neurotoxic neurotoxicity novel penclomedine pre-clinical preclinical study pyridine response

项目摘要

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.

描述（由申请人提供）：拟议研究的目的是使用 4-去甲基-胆固醇氧基羰基喷氯米定 (DM-CHOC-PEN)（一种 4-去甲基-喷氯米定 (DM-PEN) 的碳酸酯衍生物）进行 1 期临床试验。晚期癌症患者。后者是喷氯米定 (PEN) 的抗肿瘤活性、非神经毒性代谢物。 PEN 在临床试验中很活跃，但具有显着的神经毒性，因此试验被取消。 DM-CHOC-PEN 是作为衍生物合成的，可以穿过血脑屏障且无毒。与小鼠脑内 (IC) 植入的神经胶质瘤和乳腺癌异种移植模型相比，DM-CHOC-PEN 实现了完全缓解，并具有长期生存（且体重没有减轻）。相反，DM-PEN 在 IC 模型中没有产生完整的反应。 DM-CHOC-PEN 已完成临床前/毒理学/配方研究，正在生产中，将为临床研究做好准备。该产品将通过单剂量方案给药。 DM-CHOC-PEN 在体外与人乳腺癌外植体和神经胶质瘤细胞相比也具有活性，支持了它不需要事先激活的概念。该产品将以乳剂形式给药，该制剂在冰箱储存条件下可稳定>2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) 对晚期癌症患者进行 DM-CHOC-PEN 的 1 期评估，以确定最大耐受剂量 (MTD) 并表征相关的主要毒性。 2) 研究DM-CHOC-PEN I期临床试验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。公共健康相关性：DM-CHOC-PEN 是一种新型的 PEN 胆固醇碳酸酯衍生物，由 DEKK-TEC 设计并在南方研究所筛选。它在颅内植入的 U251 和 D54 神经胶质瘤和 MX-1 乳腺癌异种移植模型中表现出令人印象深刻的穿过 BBB 并产生 CR 和 LTS 的能力。随后，DEKK-TEC完成了临床前研究，开发了经过验证的配方，准备了IND，产品已准备好进行一期临床试验。该产品将于 07 年秋季作为乳剂投入临床使用。该项目已通过 FDA 审查 - IND 68,876。