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

 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（由申请方提供）：本项I期儿科肿瘤临床试验的主要目的是评价4-去甲基-4-胆固醇氧羰基洛美定（DM-CHOC-PEN）作为累及中枢神经系统（CNS）的晚期癌症儿童的抗癌治疗的安全性和用途。DM-CHOC-PEN是一种多氯吡啶胆固醇氧基碳酸酯，可穿过血脑屏障（BBB），在人体CNS肿瘤组织中蓄积，并产生客观缓解，具有可接受/可逆的肝毒性（在既往患有肝病的患者中），并且在成人I/II期临床试验中没有血液学、肾脏、神经毒性的证据，生活质量和总生存期改善- IND - 68，876（1-6）。FDA支持拟议的I期临床试验，旨在确定CNS癌症儿童的安全性，毒性和可接受的MTD，现在成人I期试验已经完成，毒性和MTD可接受（2，3，5，6）。中枢神经系统（CNS）的原发性恶性肿瘤占所有恶性肿瘤的不到2%，但脑肿瘤是儿童死亡的第二大常见原因（7）。一些儿童恶性肿瘤，例如，内源性弥漫性脑桥胶质瘤-位于不尝试手术的位置（8）。设计将穿过保护性血脑屏障（BBB）的药剂的关键组成部分是药剂必须容易地在脑内运输，不产生局部刺激/神经毒性，并且不会再循环回到全身循环中。IV给药后，DM-CHOC-PEN易于穿透BBB，不是转运蛋白P-糖蛋白（P-gp）的底物，并且在CNS肿瘤中显示出抗癌活性（4）。DM-CHOC-PEN在成人中有效转运至CNS肿瘤中，且无神经毒性行为改变和相关事件，这支持该药物用于患有CNS肿瘤的儿童，该儿童的大脑发育和成熟仍非常活跃，具有认知能力。在DM-CHOC-PEN治疗的累及CNS和小脑的转移性癌症成人患者中观察到的缓解（表1）也可能发生在髓母细胞瘤中，髓母细胞瘤是一种神经外胚层起源的原始小脑肿瘤，是儿童中第二常见的脑肿瘤（7，9）。因此，该药物的独特性质和缺乏毒性在成人研究中指出，值得在儿童中进行I期试验。本I期研究的具体目的是：1）在患有涉及中枢神经系统的晚期癌症的儿童中进行DM-CHOC-PEN的I期临床试验，以记录毒性，定义可接受的最大耐受剂量（MTD），并确定药物的抗癌活性。所有数据都将通过e-RAP程序传送。这将通过IND - 68.876完成。2)研究DM-CHOC-PEN和代谢物在中枢神经系统晚期癌症儿童中的药代动力学/动力学特征。3)分析数据并准备儿童II期临床试验供FDA审查。Dr. Johannes Wolff，Chief，Pediatric Oncology Department，Cleveland Clinic，Cleveland，OH将担任试验中心主任。Wolff博士是一位成熟的儿科神经肿瘤学家，有资格指导临床试验。顾问在设计科确定。