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: 10077649
• 负责人: WILLIAM MC CULLOCH
• 金额: $ 93.62万
• 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/10077649
• 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; Risk stratification; 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; 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有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.cancer.org）。BCa作为两个存在 非肌层浸润性膀胱癌（NMIBC）和肌层浸润性膀胱癌 （MIBC）。治疗NMIBC和MIBC的方法以及治疗结果相当复杂。 不同.尽管内窥镜切除术后膀胱内给予免疫治疗或 使用化疗药物时，60-70%的NMIBC会复发，20-30%的患者进展为MIBC， 其中金标准治疗是新辅助顺铂化疗，然后是根治性化疗， cyclohexane。CicloMed LLC正在开发环吡酮前药（CPX-POM），用于治疗 膀胱癌CPX-POM被快速和完全代谢为环吡酮（CPX），即活性化合物。 代谢产物并经肾脏消除，导致尿液浓度超过体外 静脉（IV）给药后IC 50增加数倍。CPX的体外活性为 在几种高级别的人尿路上皮膀胱癌细胞系中证实。体内临床前 CPX-POM的原理证明已经在一种经过验证的化学品中得到了充分证明。 致癌物小鼠膀胱癌模型。在提交研究性新药后 CicloMed LLC向美国食品药品监督管理局（FDA）提出申请， 一项在晚期乳腺癌患者中进行的多中心、首次人体、I期、开放标签、剂量递增研究 实体瘤（NCT 03348514）。19例患者入组I期试验。基于安全 和剂量耐受性，IV CPX-POM的推荐II期剂量（RP 2D）定义为900 mg/m2。该直接进入II期SBIR应用的目标是表征临床 在12例新诊断或 接受经尿道切除术（TURBT）的复发性BCa患者， 活性证明在这些患者中获得膀胱肿瘤组织，询问尿路上皮癌 CPX-POM抑制的细胞信号传导途径调节改变的患者生物标本 局单细胞测序将作为一种无偏倚的方法来表征 机会之窗研究中的药理活性和潜在作用机制 患者免疫组织化学（IHC）分析将确定CPX-POM处理对细胞增殖的影响。 增殖、Notch信号通路表达和CD 8+肿瘤淋巴细胞浸润。单个 cell sequencint将为额外的IHC分析提供信息。拟议的机会之窗审判， NMIBC患者和尿路上皮癌生物储存库的分子/遗传学研究至关重要 在30-40年设计和进行计划的2期临床概念验证试验所需的数据 可评估的高风险NMIBC患者。