A Phase I Clinical Trial: Binary Therapy with DM-CHOC-PEN and WBRT in Adults with Cancer Involving the CNS

I 期临床试验：DM-CHOC-PEN 和 WBRT 的二元疗法治疗累及中枢神经系统的癌症成人

• 批准号: 9253561
• 负责人: Lee ROY MORGAN
• 金额: $ 14.33万
• 依托单位: DEKK-TEC, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-03 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253561
• 关键词: Adenocarcinoma; Adult; Advanced Malignant Neoplasm; Adverse effects; Adverse event; Alkylating Agents; Animals; Back; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Breast Melanoma; Carrier Proteins; Clinical Investigator; Clinical Trials; Common Neoplasm; Cranial Irradiation; Cytosine; DNA Alkylation; DNA Repair; Data; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Goals; Guanine; Human; Incidence; Kidney; Lesion; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Metastatic Neoplasm to the Central Nervous System; Micrometastasis; Monitor; Non-Small-Cell Lung Carcinoma; Oncologist; Operative Surgical Procedures; P-Glycoprotein; Participant; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Primary Neoplasm; Radiation; Radiation Oncologist; Radiation therapy; Radiosurgery; Reporting; Research Design; Research Project Grants; Safety; Sampling; Therapy trial; Time; Toxic effect; adduct; anticancer activity; cancer therapy; chemotherapeutic agent; design; experience; improved; irritation; kidney cell; malignant breast neoplasm; melanoma; phase 1 study; phase I trial; prevent; radiation effect; response; sarcoma; standard of care; tumor

The goal of this Phase I clinical trial will be to document safety and potential usefulness of 4- demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in combination with de-escalating doses of whole brain radiation therapy (WBRT), as binary therapy in subjects with advanced cancer involving the CNS [a Phase I clinical trial]. DM-CHOC-PEN is a polychlorinated pyridyl cholesteryloxycarbonate, which has completed Phase I/II clinical trials in adults with advanced cancer involving the CNS. Objective responses, improved PFS/OS and acceptable toxicities have been observed primarily in lung and breast cancers, melanoma and sarcoma malignancies involving the CNS. The incidence of metastatic cancer involving the CNS was >220,000 cases in the US alone in 2015, >20 times the incidence of high grade GBM. The four most common tumor types to develop CNS metastases were lung > breast > melanoma > renal cell – 1,2,3,4, with median survival worse than those reported for primary CNS malignancies – 8 months vs. 13 months for GBM. Radiation (RT) is still the main stay of treatment in the manage of CNS metastases since the presentation is often multi-focal, surgery is not attempted and most chemotherapeutic agents do not cross the blood brain barrier (BBB). However, responses to whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) [standard of care] are of a short interval and associated with CNS side effects. Todate, the responses, tolerance and safety observed in those subjects with cancers involving the CNS that were treated with the drug, support the use of the proposed combination. DM-CHOC- PEN, an alkylating agent may also prevent DNA repair plus sensitize micrometasteses to radiation. Five (5) subjects – 4-NSCLC and 1-sarcoma involving the CNS from the Phase I/II trials received radiation (RT) post-DM-CHOC-PEN therapy without toxicity; 1-subject (NSCLC) was treated twice and now a CR; all have had excellent long term responses. Plus, support is presented that the drug accumulates in cancers involving the CNS, as well as potentiates radiation effects in human lung cancer. A critical component in designing an agent to cross the protective BBB is selecting one that will be readily transported intracerebrally, does not produce local irritation and is not rejected back into the general circulation. DM-CHOC-PEN satisfies these requires - penetrates the BBB, plus is not a substrate for the transporter protein P-glycoprotein (P-gp) and not recycled out of the CNS. No neuropsycho-performance alterations or neuro-adverse events have been attributed to the drug in either the animal studies, or in any of the adult subjects treated. DM-CHOC-PEN’s MOA is via bis-alkylation of DNA [forms adducts with N7- guanine and N4 - cytosine] with no hematological/renal toxicities observed, thus the combination should be compatible, however will be monitored closely. The specific objectives of the Phase I study will be to: 1) Conduct a Phase I clinical trial with the binary combination - DM-CHOC-PEN plus de-escalating doses of WBRT, in adults with advanced cancer involving the CNS to document safety, toxicities, define acceptable minimal effective doses (MED) for the WBRT. 2) Study the pharmacokinetic/dynamic profiles for DM-CHOC-PEN and metabolites in the presence of WBRT in adults with advanced NSCLC adenocarcinoma involving the CNS. 3) Monitor and document any anticancer activity for the binary therapy; analyze data and prepare a binary Phase II clinical trial in subjects with cancers involving the CNS [IND - 68.876]. Drs. T Mahmood, P Friedlander, RS Weiner, M Barnhill, MH Hayman, ML Ware, E Zakris and M Mehta will be the coop-clinical trial center directors. They are well-established clinical investigators, a combination of medical, radiation and neuro-oncologists, most of whom were involved in the Phase I/IItrials with DM-CHOC-PEN and are well qualified to co-direct this binary trial. Consultants are identified in the Relevant Experience Section. Plus, the FDA supports the proposed Phase I binary study.

该阶段临床试验的目的是记录4--的安全性和潜在实用性 脱甲基-4-色氧化甲苯甲列酰胺类（DM-CHOC-PEN）与降级的结合 全脑放射治疗（WBRT）的剂量，作为晚期癌症受试者的二元疗法 涉及中枢神经系统[I期临床试验]。 DM-CHOC-PEN是一种多氯化吡啶基胆固醇，已完成I/II期 涉及中枢神经系统的成年人的临床试验。客观响应，改善PFS/OS 并且已经观察到可接受的毒性主要在肺癌和乳腺癌，黑色素瘤和 CNS的肉瘤恶性肿瘤。 仅在美国，涉及CNS的转移性癌症涉及中枢神经系统的事件在2015年就> 220,000例 >高级GBM事件的20倍。开发CNS的四种最常见的肿瘤类型 转移是肺>乳腺癌>黑色素瘤>肾细胞 - 1,2,3,4，中位生存率比 报告的原发性中枢神经系统恶性肿瘤 - 8个月，而GBM的13个月。 辐射（RT）仍然是CNS转移管理的主要治疗方法以来 表现通常是多焦点的，没有尝试手术，并且大多数化学治疗剂不尝试 越过血脑屏障（BBB）。但是，对整个大脑辐射（WBRT）和 立体定向放射外科手术（SRS）[护理标准]的间隔很短，与CNS侧相关 效果。在那些涉及的癌症的受试者中观察到的反应，宽容和安全性 用药物治疗的中枢神经系统支持拟议组合的使用。 DM-Choc- 笔，烷基化剂还可以防止DNA修复以及对辐射的敏感微晶。 五（5）名受试者 - 4-NSCLC和1-核心涉及I/II期试验的CNS （RT）DM-CHOC-PEN治疗没有毒性；对1个受试者（NSCLC）进行了两次治疗，现在是CR； 所有人都有出色的长期回应。另外，支持该药物积累 涉及中枢神经系统的癌症以及人类肺癌的潜在辐射影响。 设计代理以越过受保护的BBB的关键组成部分是选择容易的组件 脑内运输，不会产生局部刺激，也不会被拒绝回到一般 循环。这些所需的DM-Choc-Pen满意度 - 穿透BBB，加上不是底物 转运蛋白P-糖蛋白（P-GP），而不是从中枢神经系统中回收的。没有神经心理绩效 在动物研究中或任何人中，改变或神经不良事件已归因于该药物 接受治疗的成年受试者。 DM-CHOC-PEN的MOA是通过DNA的双烷基化[形成N7-的加合物 鸟嘌呤和N4-胞嘧啶]没有观察到血液学/肾脏毒性，因此该组合应为 但是，将密切监视兼容。 I阶段研究的特定对象将是： 1）使用二元组合进行I期临床试验-DM-CHOC-PEN加上降级 WBRT的剂量，涉及中枢神经系统的成年人，以记录安全，战术， 为WBRT定义可接受的最小有效剂量（MED）。 2）研究在涉及CNS的晚期NSCLC腺癌的成年人中，在WBRT存在下，在WBRT存在下，DM-CHOC-PEN和代谢产物的药代动力学/动态谱。 3）监测并记录任何二进制疗法的抗癌活性；分析数据并在涉及中枢神经系统的癌症的受试者中准备二进制II期临床试验[IND -68.876]。 博士。 T Mahmood，P Friedlander，RS Weiner，M Barnhill，MH Hayman，Ml Ware，E Zakris和M Mehta 他们是公认的临床研究者， 医学，辐射和神经肿瘤学家的结合，其中大多数参与了该阶段 具有DM-Choc-Pen的I/Iitrials，并且有资格与该二元试验合作。确定顾问 在相关的经验部分。另外，FDA支持拟议的I期二元研究。