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

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

• 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
• 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

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（由申请方提供）：拟定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奥美定（DM-CHOC-PEN）的1期临床试验，DM-CHOC-PEN是4-去甲基奥美定（DM-PEN）的碳酸酯衍生物。后者是西洛梅定（PEN）的抗肿瘤活性、非神经毒性代谢产物。PEN在临床试验中具有活性，但具有显著的神经毒性，因此该试验被取消。DM-CHOC-PEN是作为一种可以穿过血脑屏障且无毒的衍生物合成的。DM-CHOC-PEN与脑内（IC）植入的胶质瘤和乳腺癌异种移植物模型相比，在小鼠中产生了完全缓解，具有长期存活（且无体重减轻）。相比之下，DM-PEN在IC模型中没有产生完全响应。DM-CHOC-PEN已完成临床前/毒理学/制剂研究，正在生产，并将准备用于临床研究。本品将通过单次给药方案给药。DM-CHOC-PEN在体外对人乳腺癌外植体和神经胶质瘤细胞也有活性，支持其不需要预先活化的概念。该产品将作为乳剂给药，该制剂在冰箱储存条件下稳定> 2年。该包装已由FDA审查- IND 68，876。本I期研究的具体目的是：1）在晚期癌症患者中进行DM-CHOC-PEN的I期评价，以确定最大耐受剂量（MTD）并描述相关主要毒性。2)研究DM-CHOC-PEN在I期临床试验中的药代动力学和药效学特征。3)评价抗肿瘤活性并以电子方式存储/分析数据。公共卫生关系：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。它已经证明了令人印象深刻的能力，通过血脑屏障，并产生CR和LTS颅内植入U251和D54胶质瘤和MX-1乳腺癌异种移植模型。随后，DEKK-TEC完成了临床前研究，开发了一种经过验证的配方，准备了IND，该产品已准备好进行1期临床试验。该产品将于2007年秋季作为乳剂投入临床使用。该项目已通过FDA -IND 68，876审查。