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

描述（由申请人提供）：本研究项目的主要目标是在II期临床试验中评价4-去甲基-4-胆固醇氧羰基洛美定（DM-CHOC-PEN），一种多氯胆固醇碳酸酯作为晚期癌症患者的抗癌治疗。在临床前研究期间，与颅内（IC）植入的人神经胶质瘤和乳腺癌异种移植物以及小鼠黑色素瘤模型相比，DM-CHOC-PEN产生了完全缓解，具有长期存活。在最近完成的I期临床试验（包括CNS受累的患者）中，该药物被证明无神经毒性。几个患者-肉瘤、GBM、乳腺癌（CNS病变）已经证明PFS > 6-18个月。1例（肉瘤扩散至正弦）NED × 12+ mos。未观察到肾脏、肺部和血液学副作用;剂量限制性作用为肝脏胆红素升高。审查完整的药代动力学研究/参数。临床产品是一种乳剂，在冷藏条件下稳定性为1.5年。包装已由IRB和FDA审查- IND 68，876。目标将包括：1）启动II期试验，IV给予晚期或复发性癌症患者DM-CHOC-PEN（+/- CNS受累可接受），并验证拟定剂量可接受，监测药效学和毒性。2)根据RECIST指南进行成像/检查，监测DM-CHOC-PEN的肿瘤反应。3)以电子方式存储/分析毒性、反应和肿瘤-器官关系的临床数据。4)尽可能继续储存治疗前和治疗后患者的肿瘤组织，并测定肿瘤药物/代谢物含量和生物标志物;储存血液样本用于未来研究，即Caris Target Now等。5）准备FDA演示文稿，用于在特定肿瘤类型患者中进行的后续II期（二元药物）或III期（单一药物）DM-CHOC-PEN试验。

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.