Development of Ciclopirox Prodrug as a Novel Systemic Treatment for High-Risk Non-Muscle Invasive Bladder Cancer

开发环吡酮前药作为高风险非肌肉浸润性膀胱癌的新型全身治疗方法

• 批准号: 10259776
• 负责人: WILLIAM MC CULLOCH
• 金额: $ 97.64万
• 依托单位: CICLOMED, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259776
• 关键词: Affect; Aftercare; American Cancer Society; Biological Markers; Bladder Neoplasm; Bladder Urothelium; CD8B1 gene; Cancer Center; Cancer Patient; Cancer cell line; Cell Proliferation; Cells; Cisplatin; Clinical; Clinical Pharmacology; Clinical Trials; Cohort Studies; Consent; Data; Databases; Development; Diagnosis; Disease; Disease Progression; Dose; Down-Regulation; Enrollment; Evaluable Disease; Excision; Goals; Gold; Human; Immunohistochemistry; Immunotherapy; In Vitro; Infiltration; Intravenous; Intravesical Administration; Investigational New Drug Application; Kansas; Kidney; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical center; Molecular Genetics; Neoadjuvant Therapy; Newly Diagnosed; Notch Signaling Pathway; Patient-Focused Outcomes; Patients; Pharmacology; Phase; Prodrugs; Proteins; Radical Cystectomy; Recurrence; Registries; Regulation; Regulatory Pathway; Safety; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Solid Neoplasm; Specimen; Techniques; The Cancer Genome Atlas; Tissues; Transurethral Resection; Treatment outcome; Tumor Tissue; United States Food and Drug Administration; Universities; Urinary tract; Urine; Urothelium; base; biobank; chemical carcinogen; chemotherapy; circulating biomarkers; design; drug action; first-in-human; gamma secretase; high risk; in vitro activity; in vivo; lymphoid neoplasm; mouse model; muscle invasive bladder cancer; neoplasm registry; nicastrin protein; non-muscle invasive bladder cancer; notch protein; novel; open label; pharmacokinetics and pharmacodynamics; phase I trial; pre-clinical; presenilin-1; risk stratification; single cell sequencing; standard care; standard of care; treatment duration

Project Summary The American Cancer Society estimates ~80,470 patients will be diagnosed with bladder cancer (BCa) and ~17,670 will die of the disease in the US this year (www.cancer.org). BCa exists as two diseases, non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Approaches to treating NMIBC and MIBC, as well as treatment outcomes, are quite different. Despite endoscopic resection followed by intravesical administration of immunotherapy or chemotherapy agents, 60-70% of NMIBC will recur with 20-30% of patients progressing to MIBC, where the gold standard treatment is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. CicloMed LLC is developing Ciclopirox Prodrug (CPX-POM) for the treatment of bladder cancer. CPX-POM is rapidly and completely metabolized to ciclopirox (CPX), the active metabolite and undergoes renal elimination resulting in urine concentrations that exceed in vitro IC50's several-fold following intravenous (IV) administration. In vitro activity of CPX was demonstrated in several high-grade human urothelial bladder cancer cell lines. In vivo preclinical proof of principle for CPX-POM has been thoroughly demonstrated in a validated, chemical carcinogen mouse model of bladder cancer. Following submission of an investigational new drug application to the US Food and Drug Administration (FDA), CicloMed LLC conducted a US multicenter, First-in-Human, Phase 1, open-label, dose escalation study in patients with advanced solid tumors (NCT03348514). Nineteen patients were enrolled in the Phase 1 trial. Based on safety and dose tolerance, the Recommended Phase 2 Dose (RP2D) for IV CPX-POM is defined as 900 mg/m2. The goals of this Direct to Phase II SBIR application are to characterize the clinical pharmacology of the IV CPX-POM RP2D in a window of opportunity study of 12 newly diagnosed or recurrent BCa patients undergoing transurethral resection (TURBT), and based pharmacologic activity demonstrated bladder tumor tissues obtained in these patients, interrogate urothelial cancer patient biospecimens for altered regulation of cell signaling pathways inhibited by CPX-POM administration. Single cell sequencing will be employed as an unbiased approach to characterizing pharmacologic activity and potential mechanisms of action in the window of opportunity study patients. Immunohistochemistry (IHC) analyses will determine effects of CPX-POM treatment on cell proliferation, Notch signaling pathway expression, and CD8+ tumor lymphocyte infiltration. Single cell sequencint will inform additional IHC analyses. The proposed window of opportunity trial in NMIBC patients and molecular/genetic interrogation of urothelial cancer biorepository are critical data needed to design and conduct the planned Phase 2 clinical proof of concept trial in 30-40 evaluable high-risk NMIBC patients.

项目摘要 美国癌症协会估计约80,470名患者将被诊断为膀胱癌 (BCA)，今年美国将有17,670人死于这种疾病(www.ancer.org)。BCA以两种形式存在 疾病、非肌肉浸润性膀胱癌(NMIBC)和肌肉浸润性膀胱癌 (MIBC)。治疗NMIBC和MIBC的方法以及治疗结果相当 不一样。尽管在内窥镜下切除，然后在膀胱内注射免疫治疗或 化疗药物，60%-70%的NMIBC将复发，20%-30%的患者进展为MIBC， 其中金标准治疗是新辅助顺铂为主的化疗，然后是根治性治疗 膀胱切除术。CicloMed LLC正在开发环丙沙星前药(CPX-POM)，用于治疗 膀胱癌。环磷酰胺(CPX-POM)被迅速而完全地代谢成活性物质环丙吡喃(CPX)。 代谢物，经过肾脏消除，导致尿液浓度超过体外 IC_(50)：S静脉注射多次给药。环磷酰胺的体外活性为 在几种高级别的人尿路上皮性膀胱癌细胞系中均有表达。体内临床前研究 CPX-POM的原理证明在一种经过验证的化学物质中得到了彻底的证明 致癌小鼠膀胱癌模型。在提交一种研究用新药后 向美国食品和药物管理局(FDA)申请，CicloMed LLC在美国进行了一项 晚期癌症患者的多中心、首例人类、1期、开放标签、剂量递增研究 实体瘤(NCT03348514)。19名患者参加了第一阶段试验。以安全为基础 和剂量耐受性，静脉注射CPX-POM的推荐2期剂量(RP2D)定义为900 Mg/m2。这种直接到第二阶段SBIR应用的目标是描述临床 12例初诊患者的机会窗研究中静脉注射CPX-POM RP2D的药理学 复发的BCA患者接受经尿道电切术(TURBT)和基于药物的研究 活动显示这些患者获得的膀胱癌组织，询问尿路上皮癌 CPX-POM抑制的细胞信号通路调节改变的患者生物样品 行政管理。单细胞测序将作为一种无偏见的方法来表征 机会研究窗口中的药理活性和潜在作用机制 病人。免疫组织化学(IHC)分析将确定CPX-POM处理对细胞的影响 增殖、Notch信号通路表达及CD8+肿瘤淋巴细胞浸润。单人 细胞测序将提供额外的IHC分析。建议的机会试验窗口 NMIBC患者和尿路上皮癌生物信息库的分子/遗传学查询是关键 在30-40年内设计和实施计划中的第二阶段临床概念验证试验所需的数据 可评估的高危NMIBC患者。