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

本项目的目标是进行I期临床试验，以确定II期推荐剂量 图2示出了负载有化疗药物紫杉醇（PTX）的膀胱癌靶向胶束的RP 2D。配备VA 职业发展奖-2和VA优异奖（PI：潘），我们开发了一种膀胱癌特异性靶向 名为PLZ 4的配体，以及PLZ 4涂层的载有PTX的纳米级胶束（PPM）平台，可以特异性地 在体外和体内将药物负载递送到膀胱癌细胞中。这项拟议的临床试验将进行 一项首次使用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% 诊断时的癌症病例。目前的一线治疗方法是经尿道电切术， 膀胱内滴注治疗剂，通常是卡介苗（BCG），与膀胱内分泌失调有关。 两年的复发率约为70%。派姆单抗和戊柔比星是唯一的二线药物 经美国食品药品监督管理局（FDA）批准，应答率分别为40%和20- 40%。 考虑到膀胱癌是十大最常见的癌症之一，超过70%的膀胱癌 被诊断为NMIBC，对于开发更有效的疗法存在巨大的未满足的医疗需求。这 I期试验的主要目的是确定PPM的II期推荐剂量（RP 2D）。 次要目的是评估毒性，获得PPM的初步疗效信息， 测定膀胱内滴注PPM后的全身吸收。多达25例复发性或难治性患者 将招募标准一线膀胱内治疗帕博利珠单抗治疗后的NMIBC。PPM将是 每周一次膀胱内滴注，持续6周。毒性将由NCI通用 不良事件术语标准（CTCAE）第5.0版。将通过尿细胞学检查确定疗效 两周后行膀胱镜检查。将进行分子相关性研究。

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.