4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN): A Phase II Clinica

描述(由申请人提供)：该研究项目的主要目标将是在第二阶段临床试验中评估4-去甲基-4-胆固酮-4-胆固酮(DM-CHOC-PEN)，一种多氯胆固醇碳酸酯作为晚期癌症患者的抗癌疗法。在临床前研究中，DM-CHOC-PEN在小鼠的人脑胶质瘤、乳腺癌异种移植和黑色素瘤小鼠模型中实现了完全缓解和长期存活。在最近完成的I期临床试验中(包括中枢神经系统受累的患者)，该药物被证明是无神经毒性的。几个病人--肉瘤、基底膜、乳腺癌(中枢神经系统病变)--已经表现出PFS和GT；6-18个月。1例(肉瘤扩散至正弦)为NED×12个月。未观察到肾、肺和血液学副作用；剂量限制作用是肝脏升高的胆红素。对完整的药代动力学研究/参数进行了综述。本品为乳状液，冷藏一年半，稳定性好。该方案已经由IRBs和FDA-IND 68,876进行了审查。目标将包括：1)启动DM-CHOC-PEN对晚期或复发癌症患者(/-CNS参与可接受)进行静脉注射的第二阶段试验，并验证建议的剂量是可接受的，监测药效学和毒性。2)根据RECIST指南监测肿瘤对DM-CHOC-PEN的每次成像/检查的反应。3)以电子方式存储/分析临床数据的毒性、反应和肿瘤-器官关系。4)尽可能继续保存治疗前后患者的肿瘤组织，并分析肿瘤药物/代谢物含量和生物标志物；存储血液样本，以供未来研究，如CARIS Target Now等。5)为DM-CHOC-PEN在特定肿瘤类型患者中进行后续II期(二元药物)或III期(单一药物)试验准备FDA的演示文稿。

DESCRIPTION (provided by applicant): The principal goal of this research project will be to evaluate 4-demethyl-4- cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), a polychlorinated cholesterol carbonate as anticancer therapy for patients with advanced cancer in a Phase II clinical trial. During pre-clinical studies DM-CHOC-PEN produced complete remissions with long term survival vs. intracranially (IC) implanted human gliomas and breast cancer xenograft and melanoma murine models in mice. In the recently completed Phase I clinical trial (that included patients with CNS involvement), the drug proved to be non-neurotoxic. Several patients - sarcoma, GBM, breast cancer (CNS lesions) have demonstrated PFS > 6-18 mos. and one (sarcoma spread to the sine) has NED x 12+ mos. Renal, pulmonary and hematological side effects were not observed; dose limiting effect was hepatic - elevated bilirubin. Complete pharmacokinetic studies/parameters are reviewed. The clinical product is an emulsion with stability under refrigeration - 1.5 yrs. The package has been reviewed by IRBs and FDA - IND 68,876. The aims will include: 1) Initiate a Phase II trial with DM-CHOC-PEN administered IV to patients with advanced or recurrent cancer (+/- CNS involvement acceptable) and verify that the proposed dose is acceptable, monitor pharmacodynamics and toxicities. 2) Monitor tumor responses to DM-CHOC-PEN per imaging/examinations using RECIST guidelines. 3) Electronically store/analyze clinical data for toxicity, responses and tumor-organ relationships. 4) Continue to bank tumor tissue from pre- and post-treated patients when possible and assay tumor - drug/metabolite content and bio-markers; store blood samples for future studies, i.e. Caris Target Now, etc. 5) Prepare a FDA presentation for subsequent Phase II (binary drug) or III (single drug) trials with DM-CHOC-PEN in patients with specific tumor types.