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

基本信息

批准号：
10578717
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
项目类别：
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/10578717
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 Cystoscopy Cytology Data Diagnosis Disease Progression Dose Drug Delivery Systems Drug Targeting Fibroblasts Funding Future Goals Good Manufacturing Process Grant Hour Human In Vitro Inflammation Intravesical Instillation Investigational Drugs 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 Phase Phase I Clinical Trials Population Published Comment Radical Cystectomy Recommendation Recurrence Recurrent Malignant Neoplasm Refractory Reporting Research Design Resources Safety Sample Size Secondary to Specificity Surface Therapeutic Therapeutic Agents Toxic effect Toxicology Transurethral Resection Treatment outcome Umbilicus United States United States Food and Drug Administration Urine Urothelial Cell Vascular Endothelial Cell absorption arm cancer cell cancer diagnosis cancer recurrence cell killing cohort cost effective therapy first-in-human improved in vivo intravesical manufacture nanomicelles nanoscale non-muscle invasive bladder cancer novel open label pembrolizumab phase I trial prevent recruit response systemic toxicity tumor progression

项目摘要

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）负载化疗药物紫杉醇（PTX）的膀胱癌靶向胶束和 VA。职业发展奖 2 和 VA 优异奖（PI：Pan），我们开发了膀胱癌特异性靶向药物名为 PLZ4 的配体，以及 PLZ4 包被的 PTX 负载的纳米级胶束 (PPM) 平台，该平台可以特异性地这项拟定的临床试验将在体外和体内递送至膀胱癌细胞中。使用 PPM 治疗非肌浸润性膀胱癌 (NMIBC) 的首次人体试验。 NMIBC 是美国十种最常见的癌症之一，约占膀胱癌的 75%。诊断时的癌症病例目前的一线治疗方法是经尿道切除术。治疗剂（通常是卡介苗（BCG））的膀胱内滴注与两年复发率约为 70%，Pembrolizumab 和 Valrubicin 是唯一的二线药物。经美国食品药品监督管理局 (FDA) 批准，有效率分别为 40% 和 20-40%。考虑到膀胱癌是十大最常见癌症之一，占膀胱癌的 70% 以上被诊断为 NMIBC 后，开发更有效的治疗方法还有巨大的未满足的医疗需求。拟议的 I 期试验的主要目标是确定 PPM 的推荐 II 期剂量 (RP2D)。次要目标是评估毒性，获得PPM的初步功效信息，以及确定膀胱内滴注 PPM 后的全身吸收情况，最多 25 名复发或难治性患者。标准一线膀胱内治疗后的 NMIBC 将招募 PPM 治疗。每周一次膀胱灌注，持续六周。毒性将由 NCI Common 进行评估。不良事件术语标准 (CTCAE) 5.0 版疗效将通过尿液细胞学确定。治疗结束后两周进行膀胱镜检查。