A Phase I Clinical Trial: Binary Therapy with DM-CHOC-PEN and WBRT in Adults with Cancer Involving the CNS

这项I期临床试验的目标将是记录4- 去甲基-4-胆固醇酮(DM-CHEC-PEN)联合降压 全脑放射治疗(WBRT)的剂量，作为晚期癌症患者的二元治疗 涉及CNS[一期临床试验]。 DM-CHEC-PEN是一种已完成I/II阶段的多氯吡啶胆固醇氧基碳酸酯 对累及中枢神经系统的晚期癌症成年人的临床试验。客观响应，改进PFS/OS 可接受的毒性主要见于肺癌和乳腺癌、黑色素瘤和 侵犯中枢神经系统的恶性肉瘤。 2015年，仅在美国，涉及中枢神经系统的转移性癌症的发病率就达到22万例。 &gt；是高级别GBM发病率的20倍。发生中枢神经系统疾病最常见的四种肿瘤类型 转移瘤为肺；乳房；黑色素瘤；肾细胞-1，2，3，4，中位生存期低于 报告的原发性中枢神经系统恶性肿瘤为8个月，而GBM为13个月。 放射治疗(RT)仍然是治疗中枢神经系统转移瘤的主要手段。 临床表现通常是多灶性的，不尝试手术，大多数化疗药物也不尝试。 跨越血脑屏障(BBB)。然而，对全脑辐射(WBRT)和 立体定向放射外科(SRS)[护理标准]间隔短，与中枢神经系统相关 效果。到目前为止，在癌症患者中观察到的反应、耐受性和安全性 接受该药物治疗的中枢神经系统支持使用拟议的组合。DM-CHOC- PEN是一种烷化剂，也可以防止DNA修复，并使微转移对辐射敏感。 来自I/II期试验的五(5)名受试者--4-NSCLC和1--累及中枢神经系统的肉瘤--接受了放射治疗 (RT)DM-CHO-PEN治疗后无毒性；1-受试者(NSCLC)接受两次治疗，现在是CR； 所有这些都有很好的长期反应。此外，支持药物在体内累积的说法 癌症累及中枢神经系统，并增强人类肺癌的辐射效应。 在设计一种跨越保护性血脑屏障的药剂时，一个关键的成分是选择一种容易 脑内转运，不会产生局部刺激，也不会被排斥回全身 发行量。DM-CHOC-PEN满足这些要求-穿透血脑屏障，而且不是 转运蛋白P-糖蛋白(P-gp)，不能从中枢神经系统循环出来。没有神经心理表现 无论是在动物研究中，还是在任何 接受治疗的成年受试者的比例。DM-CHOC-PEN的MOA是通过DNA的双烷基化[与N7-形成加合物- 鸟嘌呤和N4-胞嘧啶]，没有观察到血液/肾脏毒性，因此组合应该是 然而，将密切关注Compatible。 第一阶段研究的具体目标是： 1)进行二元组合-DM-CHOC-PEN+降级的I期临床试验 剂量的WBRT，在晚期癌症累及中枢神经系统的成年人中，以记录安全性、毒性、 定义WBRT的可接受最小有效剂量(MED)。 2)研究DM-CHEC-PEN及其代谢物在受累于中枢神经系统的晚期非小细胞肺癌成人患者中的药代动力学/动力学特征。 3)监测和记录二元疗法的任何抗癌活性；分析数据，并准备对涉及中枢神经系统癌症的受试者进行二期临床试验[IND-68.876]。 马哈茂德博士、P·弗里德兰德博士、RS·韦纳博士、M·巴恩希尔博士、MH·海曼博士、ML Ware博士、E·扎克里斯博士和M·梅塔博士 将是合作临床试验中心的主任。他们是久负盛名的临床研究人员， 医学、放射和神经肿瘤学家的组合，其中大多数人参与了这一阶段 I/II试验与DM-CHOC-PEN，并有很好的资格共同指导这一二元试验。确定了顾问 在相关体验部分。此外，FDA支持拟议的I阶段二元研究。

The goal of this Phase I clinical trial will be to document safety and potential usefulness of 4- demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in combination with de-escalating doses of whole brain radiation therapy (WBRT), as binary therapy in subjects with advanced cancer involving the CNS [a Phase I clinical trial]. DM-CHOC-PEN is a polychlorinated pyridyl cholesteryloxycarbonate, which has completed Phase I/II clinical trials in adults with advanced cancer involving the CNS. Objective responses, improved PFS/OS and acceptable toxicities have been observed primarily in lung and breast cancers, melanoma and sarcoma malignancies involving the CNS. The incidence of metastatic cancer involving the CNS was >220,000 cases in the US alone in 2015, >20 times the incidence of high grade GBM. The four most common tumor types to develop CNS metastases were lung > breast > melanoma > renal cell – 1,2,3,4, with median survival worse than those reported for primary CNS malignancies – 8 months vs. 13 months for GBM. Radiation (RT) is still the main stay of treatment in the manage of CNS metastases since the presentation is often multi-focal, surgery is not attempted and most chemotherapeutic agents do not cross the blood brain barrier (BBB). However, responses to whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) [standard of care] are of a short interval and associated with CNS side effects. Todate, the responses, tolerance and safety observed in those subjects with cancers involving the CNS that were treated with the drug, support the use of the proposed combination. DM-CHOC- PEN, an alkylating agent may also prevent DNA repair plus sensitize micrometasteses to radiation. Five (5) subjects – 4-NSCLC and 1-sarcoma involving the CNS from the Phase I/II trials received radiation (RT) post-DM-CHOC-PEN therapy without toxicity; 1-subject (NSCLC) was treated twice and now a CR; all have had excellent long term responses. Plus, support is presented that the drug accumulates in cancers involving the CNS, as well as potentiates radiation effects in human lung cancer. A critical component in designing an agent to cross the protective BBB is selecting one that will be readily transported intracerebrally, does not produce local irritation and is not rejected back into the general circulation. DM-CHOC-PEN satisfies these requires - penetrates the BBB, plus is not a substrate for the transporter protein P-glycoprotein (P-gp) and not recycled out of the CNS. No neuropsycho-performance alterations or neuro-adverse events have been attributed to the drug in either the animal studies, or in any of the adult subjects treated. DM-CHOC-PEN’s MOA is via bis-alkylation of DNA [forms adducts with N7- guanine and N4 - cytosine] with no hematological/renal toxicities observed, thus the combination should be compatible, however will be monitored closely. The specific objectives of the Phase I study will be to: 1) Conduct a Phase I clinical trial with the binary combination - DM-CHOC-PEN plus de-escalating doses of WBRT, in adults with advanced cancer involving the CNS to document safety, toxicities, define acceptable minimal effective doses (MED) for the WBRT. 2) Study the pharmacokinetic/dynamic profiles for DM-CHOC-PEN and metabolites in the presence of WBRT in adults with advanced NSCLC adenocarcinoma involving the CNS. 3) Monitor and document any anticancer activity for the binary therapy; analyze data and prepare a binary Phase II clinical trial in subjects with cancers involving the CNS [IND - 68.876]. Drs. T Mahmood, P Friedlander, RS Weiner, M Barnhill, MH Hayman, ML Ware, E Zakris and M Mehta will be the coop-clinical trial center directors. They are well-established clinical investigators, a combination of medical, radiation and neuro-oncologists, most of whom were involved in the Phase I/IItrials with DM-CHOC-PEN and are well qualified to co-direct this binary trial. Consultants are identified in the Relevant Experience Section. Plus, the FDA supports the proposed Phase I binary study.