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

 描述(申请人提供)：这项第一阶段儿科肿瘤学临床试验的主要目标将是评估4-demethyl-4-cholesteryloxycarbonylpenclomedine(DM-CHEC-PEN)作为晚期癌症儿童中枢神经系统(CNS)的抗癌疗法的安全性和用途。DM-CHOC-PEN是一种多氯吡啶胆固醇氧碳酸酯，它跨越血脑屏障(BBB)，在人类中枢神经系统肿瘤组织中蓄积，并已产生客观反应，具有可接受的/可逆的肝脏毒性(在既往肝病患者中)，在成人I/II期临床试验中没有证据表明血液、肾脏、神经毒性可改善生活质量和总体存活率-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，因为成人I期试验已经完成，毒性可接受，并确定了MTDS(2，3，5，6)。中枢神经系统(CNS)原发恶性肿瘤在所有恶性肿瘤中所占比例不到2%，但脑瘤是儿童第二大常见死因(7)。一些儿童恶性肿瘤，如固有的弥漫性脑桥胶质瘤，其位置不适合手术治疗。在设计跨越保护性血脑屏障(BBB)的试剂时，一个关键的组成部分是该试剂必须易于在大脑内转运，不会产生局部刺激/神经毒性，并且不会再循环进入全身循环。静脉给药后，DM-CHOC-PEN很容易穿透血脑屏障，不是转运蛋白P-糖蛋白(P-gp)的底物，并在中枢神经系统肿瘤中显示出抗癌活性(4)。在没有神经毒性行为改变和相关事件的成人中，DM-CHOC-PEN有效地转移到中枢神经系统肿瘤中，这支持了这种药物在大脑发育和成熟仍然非常活跃的认知能力非常活跃的儿童中枢神经系统肿瘤中的使用。在接受DM-ChocPEN(表1)治疗的累及中枢神经系统和小脑的转移性癌症的成人患者中，观察到的反应也可能发生在髓母细胞瘤中，这是一种起源于神经外胚层的原始小脑肿瘤，是儿童中第二常见的脑瘤(7，9)。因此，这种药物的独特性质和成人研究中指出的无毒性值得在这里提出的儿童第一阶段试验中使用。这项第一阶段研究的具体目标将是：1)对患有中枢神经系统晚期癌症的儿童进行DM-CHOC-PEN的第一阶段临床试验，以记录毒性，确定可接受的最大耐受剂量(MTD)，并确定该药物的抗癌活性。所有数据都将通过电子说唱程序进行交流。这将通过IND-68.876完成。2)研究DM-CHEC-PEN及其代谢物在累及中枢神经系统的晚期癌症患儿中的药代动力学/动力学特征。3)分析数据并准备儿童二期临床试验，供FDA审查。俄亥俄州克利夫兰诊所儿科肿瘤科主任约翰尼斯·沃尔夫博士将担任试验地点主任。沃尔夫医生是一位资深的儿科神经肿瘤学家，有资格指导这项临床试验。在设计科确定了顾问。

 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.