4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN: A Phase II Clinical Trial in Adolescents/Young Adults (AYA)with CNS Malignancies

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN：针对患有中枢神经系统恶性肿瘤的青少年/年轻人 (AYA) 的 II 期临床试验

• 批准号: 9791343
• 负责人: Lee ROY MORGAN
• 金额: $ 51.95万
• 依托单位: DEKK-TEC, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791343
• 关键词: 20 year old; Adolescent; Adolescent and Young Adult; Adult; Advanced Malignant Neoplasm; Adverse event; Age; Age-Years; Animals; Antineoplastic Agents; Back; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Banks; Blood Circulation; Blood specimen; Brain; Brain Neoplasms; Cancer Etiology; Cancer Histology; Carbonates; Carrier Proteins; Cause of Death; Central Nervous System Neoplasms; Cessation of life; Childhood; Clinical; Clinical Data; Clinical Investigator; Clinical Trials; Cytosine; DNA Alkylation; Development; Diagnosis; Disease remission; Dose; Female; Future; Goals; Guanine; Guidelines; Healthcare; Hematologist; Hematology; Hepatotoxicity; Image; Incidence; Individual; Kidney; Malignant Neoplasms; Medical; Medical Oncologist; Monitor; Nervous system structure; Non-Small-Cell Lung Carcinoma; Oncologist; Orphan Drugs; P-Glycoprotein; Patients; Pediatric Oncologist; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Population; Recording of previous events; Reporting; Research Project Grants; Role; Source; Spinal; Toxic effect; Tumor Bank; Tumor Tissue; Urine; adduct; age group; aged; cancer therapy; cancer type; design; experience; falls; irritation; leukemia; lipophilicity; male; melanoma; neurotoxicity; pharmacokinetics and pharmacodynamics; phase 1 study; phase I trial; phase II trial; pyridine; relating to nervous system; response; sarcoma; trend; tumor; young adult

Abstract – The goal of this Phase II clinical trial application will be to evaluate 4-demethyl-4- cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as anticancer therapy for adolescents and young adults (AYA) with cancer involving the brain in a Phase II clinical trial. DM-CHOC-PEN (Fig. 1) is a polychlorinated pyridine cholesteryl carbonate (Fig. 1) that is lipophilic, electrically neural, is able to cross the blood brain barrier (BBB), localizes in CNS tumors with MOAs – alkylation of DNA @ N7 – guanine and is not transported out of the brain via Pgp (p-glycoprotein). The drug fulfills all the criteria to be a CNS active anticancer agent and recently received Orphan Drug Designation approval as therapy for NSCLC involving the CNS. The drug will complete a Phase I clinical trial in AYA subjects with advanced cancer 1st quarter – 2018 - IND 68,876. Objective responses, acceptable toxicities and no evidence of neurotoxicity have been noted in the AYA Phase I trial involving subjects with cancers involving the CNS. Hepatic toxicity that was observed in the adult Phase I trial has not been observed with the AYA subjects. Novelty and Potential Clinical Advantage – Current reviews report that almost 700,000 people in the US are living with brain or CNS tumors. Nearly 15% of these tumors involve the adolescent/young adult (AYA) population, aged 15-39 years of age. It is predicted that 10,617 AYA individuals will be diagnosed with brain or CNS tumors resulting in 434 deaths this year. For males and female individuals <20 years of age, primary brain and central nervous system tumors are the most common causes of death from cancer and in the 20-39 year age group the first cause of cancer-related deaths in males and the fifth cause of cancer-related deaths in females. However, the incidence and histology of cancer types vary according to subject age. Trends in CNS tumors have sharply increased since 1989 for AYA individuals with a history of cancer, who appeared to have ‘beaten the odds’ to have a reoccurrence from cancer, only to develop involvement in the CNS after years of remission. The aims will include: 1) Initiation of a Phase II trial with DM-CHOC-PEN administered IV to AYA subjects with cancer involving the CNS and/or spinal nervous systems (SNS) and varication that the proposed doses are acceptable, monitor pharmacokinetics/pharmacodynamics and toxicities. 2) Monitor tumor responses per imaging/examinations using RECIST guidelines. 3) Electronically store/analyze clinical data for responses, toxicity, and PK relationships. 4) Continue to bank blood and tumor tissue from pre- and post-treated patients when possible tumor tissue assays for tumor - drug/metabolite content and bio-markers; for future studies. 5) Prepare a FDA Orphan Drug Designation (ODD) presentation/application for DM-CHOC-PEN as therapy for AYA subjects with malignancies involving the CNS/SNS. 6) Manage a platform to provide support information for AYA subjects with CNS/SNS malignancies. Thus, DEKK-TEC’S goal continues to be the development of DM-CHOC-PEN as therapy for subjects with cancer, with an emphasis on primary or metastatic central and spinal nervous system involvement. The present study will involve documenting that DM-CHOC-PEN has a role in treating AYA subjects with cancer involving the CNS or SNS and bringing together a team that can design a complete management approach – a ‘platform’ for support sources that can be disseminated to these individuals that ‘often fall through the cracks’ of health care and are not treated appropriately because of their age deferential – too old for pediatric oncologists and too young for conventional medical oncologists.

摘要 – 该 II 期临床试验申请的目标是评估 4-demethyl-4- 胆固醇氧羰基喷氯米定 (DM-CHOC-PEN) 作为青少年和青少年的抗癌治疗 II 期临床试验中患有脑部癌症的年轻人 (AYA)。 DM-CHOC-PEN（图 1）是一种多氯化吡啶胆固醇碳酸酯（图 1），具有亲脂性， 电神经，能够穿过血脑屏障 (BBB)，定位于具有 MOA 的中枢神经系统肿瘤 – DNA @ N7 – 鸟嘌呤的烷基化，不通过 Pgp（p-糖蛋白）转运出大脑。 该药物满足中枢神经系统活性抗癌药物的所有标准，并且最近获得了孤儿药资格 指定用于治疗累及中枢神经系统的非小细胞肺癌。 该药物将于 2018 年第一季度完成针对晚期癌症 AYA 受试者的 I 期临床试验 - IND 68,876。已获得客观反应、可接受的毒性且没有神经毒性的证据。 在涉及中枢神经系统癌症受试者的 AYA I 期试验中指出， 在成人 I 期试验中观察到的现象尚未在 AYA 受试者中观察到。 新颖性和潜在的临床优势 – 目前的评论报告称，近 700,000 人 美国人患有脑部或中枢神经系统肿瘤，其中近 15% 涉及青少年/年轻人。 年龄在 15-39 岁之间的 AYA 人口 预计将有 10,617 名 AYA 人。 今年，被诊断患有脑部或中枢神经系统肿瘤的男性和女性有 434 人死亡。 <20岁以下，原发性脑和中枢神经系统肿瘤是最常见的原因 癌症死亡，在 20-39 岁年龄组中是男性癌症相关死亡的首要原因 然而，癌症的发病率和组织学是女性癌症相关死亡的第五大原因。 自 1989 年以来，AYA 中枢神经系统肿瘤的趋势急剧增加。 有癌症病史的人，似乎“克服了癌症复发的可能性” 来自癌症，仅在多年缓解后才发展为中枢神经系统受累。 目标将包括： 1) 启动 II 期试验，向患有癌症的 AYA 受试者静脉注射 DM-CHOC-PEN 涉及中枢神经系统和/或脊髓神经系统 (SNS) 以及建议剂量的变化 可接受，监测药代动力学/药效学和毒性。 2) 使用 RECIST 指南监测每次成像/检查的肿瘤反应。 3) 以电子方式存储/分析反应、毒性和 PK 关系的临床数据。 4) 在可能的情况下，继续储存治疗前和治疗后患者的血液和肿瘤组织 肿瘤组织检测——药物/代谢物含量和生物标志物；用于未来研究。 5) 准备 DM-CHOC-PEN 的 FDA 孤儿药指定 (ODD) 介绍/申请，如下 治疗患有涉及 CNS/SNS 的恶性肿瘤的 AYA 受试者。 6) 管理一个平台，为患有 CNS/SNS 恶性肿瘤的 AYA 受试者提供支持信息。 因此，DEKK-TEC 的目标仍然是开发 DM-CHOC-PEN 作为受试者的治疗方法 癌症，重点是原发性或转移性中枢和脊髓神经系统受累。 本研究将涉及记录 DM-CHOC-PEN 在治疗 AYA 受试者中的作用 患有累及 CNS 或 SNS 的癌症，并组建一个可以设计完整的团队 管理方法——一个可以传播给这些人的支持来源的“平台” “经常被忽视”的医疗保健，并且由于年龄而得不到适当的治疗 恭敬——对于儿科肿瘤学家来说太老了，而对于传统医学肿瘤学家来说又太年轻了。