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（通过应用程序提供）：IT小儿肿瘤学临床试验的主要目标WILS和DE 4-DE甲基-4-胆固醇甲苯丙胺Lpenclomedine（DM-CHOC-PEN），作为涉及中心神经系统（中心神经系统的晚期癌症儿童）（ CNS）。 -INDS -68,876（1-6）。FDA支持IS临床试验，旨在识别CNS癌儿童的安全性，毒性和可接受的MTD。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）。位于未尝试的手术中（8）。 （4）DM-CHOC-PEN在成年人中的CNS肿瘤中的有效运输和相关的事件，该药物在CNS肿瘤的儿童中使用的时代仍具有认知能力。成年人涉及中枢神经系统和小脑DM-CHOC-PEN（表1）的concancancancater也可能发生在髓母细胞瘤中，儿童第二大最常见的脑肿瘤（7，9）。在这里进行的试验。 RAP计划将通过IND-68.876进行ACTH。审查。