Phase 1/2 Study of Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder - (ADAPT-BLADDER)

现代免疫疗法治疗 BCG 复发性膀胱尿路上皮癌的 1/2 期研究 - (ADAPT-BLADDER)

• 批准号: 9762315
• 负责人: Noah M Hahn
• 金额: $ 65.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762315
• 关键词: Acute; Aftercare; Alternative Therapies; Antigens; Attenuated; BCG Live; Bacillus Calmette-Guerin Therapy; Bladder; Bladder Neoplasm; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Patient; Cell surface; Cells; Clinical; Clinical Trials; Clone Cells; Combination immunotherapy; Combined Modality Therapy; Cystectomy; Data; Diagnosis; Disease; Eligibility Determination; Enrollment; External Beam Radiation Therapy; Future; Gene Expression Profile; Genomics; Goals; Immune; Immune checkpoint inhibitor; Immunotherapy; Impairment; Individual; Innate Immune Response; Intravesical Administration; Investigation; Life; MHC Class II Genes; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Methods; Modernization; Mutate; Mutation; Natural Killer Cells; Outcome; PDCD1LG1 gene; Pathway interactions; Patient Selection; Patients; Peptide Library; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phase III Clinical Trials; Population; Prediction of Response to Therapy; Public Health; Quality of life; Radiation; Recurrent tumor; Regimen; Relapse; Research; Resistance; SLEB2 gene; Safety; Sampling; Site; Solid Neoplasm; T cell response; T-Lymphocyte; Therapeutic; Tissue Sample; Toxic effect; Transitional Cell Carcinoma; Transurethral Resection; Tumor Antigens; Tumor-associated macrophages; adaptive immune response; antigen-specific T cells; arm; bladder transitional cell carcinoma; checkpoint therapy; clinical efficacy; clinical practice; design; exome; genomic biomarker; genomic signature; high risk; improved; innovation; interest; mycobacterial; nano-string; neoantigens; neutrophil; non-muscle invasive bladder cancer; novel; novel therapeutic intervention; novel therapeutics; phase 3 study; phase change; point of care; point-of-care diagnostics; precision medicine; predictive signature; prospective; recruit; relapse patients; response; standard care; targeted treatment; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor DNA; tumor immunology; tumor microenvironment

Project Summary: Over 81,000 new individuals are diagnosed each year with urothelial carcinoma (UC) of the bladder and 17,000 will die from their disease. Most have non-muscle invasive disease (NMIBC) at diagnosis. Despite standard treatment with the live, attenuated mycobacterial strain Bacillus Calmette-Guerin (BCG) instilled into the bladder, two-thirds of NMIBC patients will develop relapsed tumors after BCG treatment. While curative, cystectomy is associated with life-altering quality of life impact and is not feasible, or is refused, in many. Nonsurgical curative options for BCG-relapsing NMIBC patients are lacking. In metastatic UC, durable responses with low toxicity rates have been observed with checkpoint inhibitor (CPI) therapies aimed at the programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) pathway leading to the FDA approval of five agents. Examining novel combination approaches including CPIs in BCG-relapsing NMIBC represents a natural next step. In this proposal, we plan to define the safety and clinical activity, assess the point-of-care diagnostic potential of several genomic biomarker platforms, and perform initial mechanistic investigations of novel combinations of CPI therapy with both BCG and radiation in the multi-arm, multi-stage ADAPT-BLADDER phase 1b/2 clinical trial, with the long-term goal of informing the design of future practice-changing phase 3 trials. Objectives: 1) To demonstrate safety and clinical efficacy of immunotherapy combination regimens in patients with BCG-relapsing NMIBC; 2) To identify conserved candidate genomic signatures associated with clinical benefit and/or treatment resistance to novel immunotherapy regimens in NMIBC patients with recurrent tumors after prior BCG therapy; 3) To demonstrate the existence of tumor antigen-specific T-cell responses and correlate such responses with clinical outcomes to novel immunotherapy regimens in NMIBC patients with recurrent tumors after prior BCG therapy. Methods: We will assess each objective prospectively through the multi-center phase 1 b / 2 ADAPT- BLADDER trial in over 170 patients with BCG-relapsing NMIBC. Specifically, we will document the safety of each regimen in phase 1 and clinical efficacy in phase 2. We will correlate baseline and post- treatment genomic biomarker signatures with clinical benefit. Lastly, we will interrogate the ability of personalized neoantigen peptide libraries to expand antigen-specific T-cell clones. We hypothesize that immunotherapy combination regimens will be safe and effective. Moreover, we anticipate the identification of point-of-care genomic biomarker signatures that can distinguish patients most likely to benefit; we expect to identify novel gene expression signatures predictive of therapy response and resistance; and we suspect the planned functional tumor immunology investigations will yield illuminating discoveries.

项目概述：每年有超过81，000名新患者被诊断患有尿路上皮癌 (UC)17,000人将死于这种疾病大多数患有非肌肉侵入性疾病 （NMIBC）诊断时。尽管用活的减毒分枝杆菌菌株芽孢杆菌进行标准治疗， 卡介苗（BCG）注入膀胱，三分之二的NMIBC患者会复发 BCG治疗后的肿瘤虽然有治疗作用，但cytokine与改变生活质量有关 影响，是不可行的，或被拒绝，在许多。BCG复发NMIBC的非手术治疗选择 患者缺乏。在转移性UC中，观察到低毒性率的持久反应， 针对程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡蛋白1（PD-1）的检查点抑制剂（CPI）疗法 死亡配体1（PD-L1）通路导致FDA批准了五种药物。检查新组合 在BCG复发的NMIBC中包括CPI的方法代表了自然的下一步。在本提案中，我们 计划定义安全性和临床活性，评估几种基因组药物的床旁诊断潜力 生物标志物平台，并进行CPI治疗的新组合的初步机制研究 在多组、多阶段ADAPT-BLADDER 1b/2期临床试验中， 其长期目标是为未来改变实践的III期试验的设计提供信息。 目的：1）证明免疫治疗联合方案在儿童中的安全性和临床疗效。 BCG复发性NMIBC患者; 2）为了鉴定与NMIBC相关的保守候选基因组特征， 复发性NMIBC患者对新型免疫治疗方案的临床获益和/或治疗耐药性 3）证明肿瘤抗原特异性T细胞应答的存在， 将这些反应与NMIBC患者中新型免疫治疗方案的临床结果相关联， 既往BCG治疗后复发的肿瘤。 方法：我们将通过多中心I期B /II期ADAPT前瞻性评估每个目标， 在170多名BCG复发性NMIBC患者中进行的膀胱试验。具体来说，我们将记录 第1阶段的每种方案和第2阶段的临床疗效。我们会将基线和术后- 具有临床益处的治疗基因组生物标志物特征。最后，我们将询问 个性化的新抗原肽文库以扩增抗原特异性T细胞克隆。 我们假设免疫治疗联合方案将是安全有效的。而且我们 预测可以区分患者的即时基因组生物标志物特征的识别 最有可能受益;我们希望确定新的基因表达特征预测治疗 反应和耐药性;我们怀疑计划的功能性肿瘤免疫学研究将 产生了启发性的发现