A Phase I trial of cancer-targeting micelles for non-myoinvasive bladder cancer

癌症靶向胶束治疗非肌浸润性膀胱癌的 I 期试验

• 批准号: 10426035
• 负责人: CHONG-XIAN PAN
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426035
• 关键词: Address; Amino Acid Sequence; BCG Live; Binding; Biopsy; Biopsy Specimen; Bladder; Blood Cells; Cancer Patient; Canis familiaris; Cells; Chemistry; Clinical Research; Clinical Trials; Clinical Trials Design; Common Terminology Criteria for Adverse Events; Conduct Clinical Trials; Consultations; Correlative Study; Cyclic GMP; Cystoscopy; Cytology; Data; Diagnosis; Disease Progression; Dose; Drug Delivery Systems; Drug Targeting; Fibroblasts; Funding; Future; Goals; Grant; Hour; Human; In Vitro; Inflammation; Intravesical Instillation; Investigational New Drug Application; K-Series Research Career Programs; Ligands; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maximum Tolerated Dose; Measures; Medical; Methods; Micelles; Minor; Molecular; Names; Newly Diagnosed; Paclitaxel; Patient Care; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Published Comment; Radical Cystectomy; Recurrence; Refractory; Reporting; Research Design; Resources; Safety; Sample Size; Secondary to; Specificity; Surface; Therapeutic Agents; Toxic effect; Transurethral Resection; Treatment outcome; United States; United States Food and Drug Administration; Urine; Urothelial Cell; Vascular Endothelial Cell; absorption; arm; base; cancer cell; cancer diagnosis; cancer recurrence; cell killing; cohort; cost; effective therapy; first-in-human; improved; in vivo; intravesical; nanomicelles; nanoscale; non-muscle invasive bladder cancer; novel; open label; patient population; pembrolizumab; phase I trial; prevent; recruit; response; study population; systemic toxicity; tumor progression

The goal of this project is to conduct a Phase I clinical trial to determine the recommended Phase II dose (RP2D) of bladder cancer-targeting micelles loaded with a chemotherapeutic drug paclitaxel (PTX). With a VA Career Development Award-2 and VA Merit grant (PI: Pan), we developed a bladder cancer-specific targeting ligand named PLZ4, and a PLZ4-coated PTX-loaded nanoscale micelle (PPM) platform that can specifically deliver the drug load into bladder cancer cells both in vitro and in vivo. This proposed clinical trial is to conduct a first-in-human trial to use PPM for the treatment of non-myoinvasive bladder cancer (NMIBC). Bladder cancer is one of the ten most common cancers in the United States. NMIBC accounts for around 75% of bladder cancer cases at diagnosis. The current first-line treatment approach of transurethral resection followed by intravesical instillation of therapeutic agents, usually Bacillus Calmette-Guérin (BCG), is associated with a recurrence rate of around 70% at two years. Pembrolizumab and valrubicin are the only second-line drug approved by the Food and Drug Administration (FDA) with a response rate of 40% and 20-40%, respectively. Considering that bladder cancer is among the top ten most common cancers and over 70% of bladder cancers are diagnosed as NMIBC, there are huge unmet medical needs for developing more effective therapies. This primary objective of the proposed Phase I trial is to determine the recommended Phase II dose (RP2D) of PPM. The secondary objectives are to assess the toxicity, obtain preliminary efficacy information of PPM, and determine systemic absorption after intravesical instillation of PPM. Up to 25 patients with recurrent or refractory NMIBC after a standard first-line intravesical therapy pembrolizumab treatment will be recruited. PPM will be given as intravesical instillation once weekly for six weeks. The toxicity will be assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The efficacy will be determined by urine cytology and cystoscopy two weeks after finishing treatment. Molecular correlative studies will be performed.

该项目的目标是进行I期临床试验，以确定推荐的II期剂量 (RP2D)载化疗药物紫杉醇(PTX)的膀胱癌靶向胶束。有退伍军人事务部 职业发展奖-2和VA功勋奖(PI：PAN)，我们开发了一种针对膀胱癌的靶向 名为PLZ4的配体，以及PLZ4包裹的PTX负载纳米胶束(PPM)平台，该平台可以特异性地 在体外和体内将药物负载输送到膀胱癌细胞。这项拟议的临床试验将进行 首次使用PPM治疗非肌浸润性膀胱癌(NMIBC)的人体试验。膀胱癌 是美国十大最常见的癌症之一。NMIBC约占膀胱的75% 确诊时的癌症病例。目前的一线治疗方法是经尿道电切术后再手术 治疗药物的膀胱内注射，通常是卡介苗(BCG)，与 两年后复发率约为70%。Pembrolizumab和Valruicin是唯一的二线药物 由美国食品和药物管理局(FDA)批准，应答率分别为40%和20%-40%。 考虑到膀胱癌是最常见的十大癌症之一，超过70%的膀胱癌 在被诊断为NMIBC的情况下，开发更有效的治疗方法有巨大的未得到满足的医疗需求。这 拟议的第一阶段试验的主要目标是确定PPM的推荐第二阶段剂量(RP2D)。 次要目标是评估PPM的毒性，获得初步疗效信息，以及 测定膀胱内滴注PPM后的全身吸收。多达25名复发或难治性患者 NMIBC在标准的一线膀胱内治疗后，将招募培溴利珠单抗治疗。Ppm将是 每周一次膀胱内滴注，连续六周。毒性将由NCI Common进行评估 不良事件术语标准(CTCAE)5.0版。疗效将通过尿细胞学来确定。 治疗结束后两周行膀胱镜检查。将进行分子相关研究。