Phase I Clinical trial with 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in Children with Cancer Involving the CNS

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) 在儿童中枢神经系统癌症中的 I 期临床试验

• 批准号: 9047161
• 负责人: Lee ROY MORGAN
• 金额: $ 9.04万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047161
• 关键词: Accounting; Adolescent; Adult; Advanced Malignant Neoplasm; Age; Animals; Back; Behavior Therapy; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Carrier Proteins; Cause of Death; Central Nervous System Neoplasms; Cerebellar Neoplasms; Cerebellum; Child; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; Cytosine; DNA Alkylation; Data; Data Analyses; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disseminated Malignant Neoplasm; Drug Kinetics; Drug usage; Event; Goals; Growth; Guanine; Hepatotoxicity; Human; Impairment; Kidney; Liver diseases; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of central nervous system; Malignant neoplasm of cerebellum; Maximum Tolerated Dose; Monitor; Neuraxis; Operative Surgical Procedures; P-Glycoprotein; Patients; Pediatric Oncology; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Property; Qualifying; Quality of life; Radiation; Radiation therapy; Recycling; Research Project Grants; Safety; Secondary to; Site; Toxic effect; Tumor Tissue; adduct; anticancer activity; cancer therapy; chemotherapy; cognitive ability; cognitive function; design; experience; improved; irritation; medulloblastoma; neurotoxic; neurotoxicity; phase 1 study; phase I trial; phase II trial; programs; public health relevance; pyridine; response; Accounting; Adolescent; Adult; Advanced Malignant Neoplasm; Age; Animals; Back; Behavior Therapy; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Carrier Proteins; Cause of Death; Central Nervous System Neoplasms; Cerebellar Neoplasms; Cerebellum; Child; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; Cytosine; DNA Alkylation; Data; Data Analyses; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disseminated Malignant Neoplasm; Drug Kinetics; Drug usage; Event; Goals; Growth; Guanine; Hepatotoxicity; Human; Impairment; Kidney; Liver diseases; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of central nervous system; Malignant neoplasm of cerebellum; Maximum Tolerated Dose; Monitor; Neuraxis; Operative Surgical Procedures; P-Glycoprotein; Patients; Pediatric Oncology; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Property; Qualifying; Quality of life; Radiation; Radiation therapy; Recycling; Research Project Grants; Safety; Secondary to; Site; Toxic effect; Tumor Tissue; adduct; anticancer activity; cancer therapy; chemotherapy; cognitive ability; cognitive function; design; experience; improved; irritation; medulloblastoma; neurotoxic; neurotoxicity; phase 1 study; phase I trial; phase II trial; programs; public health relevance; pyridine; response

 DESCRIPTION (provided by applicant): The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), as anticancer therapy for children with advanced cancer involving the central nervous system (CNS). DM-CHOC-PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier (BBB), accumulates in CNS tumor tissue in humans and has produced objective responses, with acceptable/reversible hepatic toxicities (in patients with prior liver disease) and no evidence of hematological, renal, neuro-toxicities with improved quality of life and overall survival in adult Phase I/II clinical trials - IND - 68,876 (1-6). The FDA supports the proposed Phase I clinical trial designed to identify safety, toxicities and an acceptable MTD in children with CNS cancers, now that the adult Phase I trial has been completed with acceptable toxicity and MTDs identified (2, 3, 5, 6). Primary malignant cancers of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the 2nd most common cause of death in children (7). Some childhood malignancies, e.g., intrinsic diffuse pontine gliomas - are located such that surgery is not attempted (8). A critical component in designing an agent that will cross the protective blood brain barrier (BBB) is that the agent must be readily transported intracerebrally, does not produce local irritation/neurotoxicity and is not recycled back into the general circulation. After IV administration DM-CHOC-PEN readily penetrates the BBB, is not a substrate for the transporter protein P-glycoprotein (P-gp) and has shown anticancer activity in CNS tumors (4). The effective transport of DM-CHOC-PEN into CNS tumors in adults without neurotoxic behavioral alterations and associated events supports the drug's use in children with CNS tumors at an age in which brain development and maturation is still very active with cognitive ability. The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM-CHOC-PEN (Table 1) may also occur in medulloblastoma, a primitive cerebellar tumor of neuroectodermal origin, that is the 2nd most common brain tumor in children (7, 9). Thus, the drug's unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in children. The specific objectives of this Phase I study will be to: 1) Conduct a Phase I clinical trial with DM-CHOC-PEN in children that have advanced cancers involving the central nervous system to document toxicities, define an acceptable maximum tolerated dose (MTD), and identify anticancer activity for the drug. All data will be communicated through an e-RAP program. This will be accomplished through IND - 68.876. 2) Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in children with advanced cancers involving the central nervous system. 3) Analyze data and prepare a Phase II clinical trial in children for FDA review. Dr. Johannes Wolff, Chief, Department of Pediatric Oncology, Cleveland Clinic, Cleveland, OH will be the trial site director. Dr. Wolff is an established pediatric neurooncologist and qualified to direct the clinical trial. Consultants are identified in the Design Section.

 描述（由适用提供）：该第一阶段儿科肿瘤学临床试验的主要目标是评估4-二甲基-4-胆汁脱甲氯乙烯甲磺酰基氯甲酰胺（DM-CHOC-PEN）的安全性和使用，作为患有中枢神经系统（CNS）儿童的抗癌治疗。 DM-CHOC-PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier (BBB), Accumulates in CNS tumor tissue in humans and has produced objective responses, with acceptable/reversible hepatitis toxicities (in patients with prior liver disease) and no evidence of hematologic, renal, neuro-toxicities with improved quality of life and overall survival in adult I/II期临床试验-IND -68,876（1-6）。 FDA支持拟议的I期临床试验，旨在识别CNS癌症儿童的安全性，毒性和可接受的MTD，现在成人I期试验已完成，并确定了可接受的毒性和MTDS（2、3、3、5、6）。中枢神经系统（CNS）的原发性恶性肿瘤占所有恶性肿瘤的2％，但脑肿瘤是儿童的第二个最常见的死亡原因（7）。某些童年的恶性肿瘤，例如内在的弥漫性蓬托胶质瘤 - 位于因此没有尝试手术（8）。设计将越过保护性血脑屏障（BBB）的试剂的关键组成部分是，必须容易地将药物室内运输，不会产生局部刺激/神经毒性，并且不会回收回到一般循环中。在静脉内施用DM-Choc-Pen之后，很容易穿透BBB，不是转运蛋白P-糖蛋白（P-GP）的底物，并且在中枢神经系统肿瘤中显示了抗癌活性（4）。在没有神经毒性行为改变的成年人中，DM-CHOC-PEN的有效运输到CNS肿瘤中，并且相关事件支持该药物在CNS肿瘤儿童中的使用，在脑发育和成熟仍然具有认知能力的年龄。观察到的反应在涉及中枢神经系统的转移性癌症和用DM-CHOC-PEN治疗的小脑的成年人中（表1）也可能发生在髓质细胞瘤中，这是神经外科的原始小脑肿瘤，这是儿童的第二大常见脑肿瘤（7，9）。这是成人研究中该药物的独特特性和缺乏毒性，值得儿童提出的第一阶段试验。本I阶段研究的具体目标将是：1）在患有中枢神经系统的儿童中，使用DM-CHOC-PEN进行I期临床试验，以记录毒性，定义可接受的最大耐受剂量（MTD），并确定该药物的抗癌活性。所有数据将通过电子说明程序传达。这将通过IND -68.876实现。 2）研究涉及中枢神经系统的晚期癌症儿童DM-CHOC-PEN和代谢产物的药代动力学/动态特征。 3）分析数据并准备儿童II期临床试验进行FDA审查。约翰内斯·沃尔夫（Johannes Wolff）博士，俄亥俄州克利夫兰克利夫兰诊所的儿科肿瘤学系主任将担任试用现场主任。沃尔夫（Wolff）博士是一位既定的儿科神经科医生，并有资格指导临床试验。顾问在设计部分中确定。