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-此二期临床试验应用的目标将是评估4-去甲基-4- 胆固醇酮(DM-CHOC-PEN)用于青少年和青少年的抗癌治疗 年轻成年人(Aya)在第二阶段临床试验中患上脑部癌症。 DM-CHOC-PEN(图1)是亲脂性的多氯化吡啶胆固醇碳酸酯(图1)， 电神经，能够穿越血脑屏障(BBB)，定位于伴有MOAs的中枢神经系统肿瘤- DNA@N7-鸟氨酸的烷基化，而不是通过PGP(P-糖蛋白)运出大脑。这个 药物符合成为中枢神经系统活性抗癌药的所有标准，最近获得了孤儿药物 指定批准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年第一季度在晚期癌症患者中完成I期临床试验 -68,876印度卢比。客观反应，可接受的毒性和没有神经毒性的证据 在涉及涉及中枢神经系统的癌症受试者的Aya I期试验中注意到。肝脏毒性 在成人I期试验中观察到，在Aya受试者中没有观察到。 新颖性和潜在的临床优势-当前的审查报告显示， 美国人患有脑瘤或中枢神经系统肿瘤。近15%的肿瘤累及青少年/青壮年。 (Aya)人口，年龄15-39岁。据预测，10,617名阿雅人将成为 被诊断出患有脑部或中枢神经系统肿瘤，导致今年434人死亡。针对男性和女性个人 20岁，原发性脑和中枢神经系统肿瘤是最常见的致病原因 癌症死亡和20-39岁年龄组男性癌症相关死亡的第一位原因 女性癌症相关死亡的第五个原因。然而，癌症的发病率和组织学 根据受试者年龄的不同，类型也有所不同。自1989年以来，Aya的中枢神经系统肿瘤的趋势急剧增加 有癌症病史的人，他们似乎克服了复发的可能性 从癌症开始，在多年的缓解后才发展到参与中枢神经系统。 这些目标将包括： 1)启动一项II期试验，对患有癌症的Aya患者进行DM-CHOC-PEN静脉注射 涉及中枢和/或脊髓神经系统(SNS)和静脉曲张 是可接受的，监测药代动力学/药效学和毒性。 2)使用RECIST指南监测每个成像/检查的肿瘤反应。 3)以电子方式存储/分析临床数据的反应、毒性和PK关系。 4)如果可能出现肿瘤，继续保存治疗前后患者的血液和肿瘤组织 肿瘤药物/代谢物含量和生物标记物的组织分析；用于未来研究。 5)为DM-CHOC-PEN准备FDA孤儿药物指定(ODD)演示/申请AS 累及CNS/SNS的AYA患者的治疗 6)管理一个平台，为患有CNS/SNS恶性肿瘤的AYA对象提供支持信息。 因此，Dekk-TEC的目标仍然是发展DM-ChocPEN作为治疗对象 对于癌症，强调原发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 癌症涉及中枢神经系统或社交网络，并汇集了一个团队，可以设计出完整的 管理方法--一个可传播给这些个人的支持来源的“平台” 由于年龄的原因，这些人往往会从医疗保健的裂缝中脱颖而出，得不到适当的治疗 恭顺-对于儿科肿瘤学家来说太老了，对于传统的内科肿瘤学家来说太年轻了。