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: 10560588
• 负责人: Noah M Hahn
• 金额: $ 59.71万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560588
• 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; Clonal Expansion; Clone Cells; Combination immunotherapy; Combined Modality Therapy; Credentialing; Cystectomy; Data; Diagnosis; Disease; Eligibility Determination; External Beam Radiation Therapy; Future; Gene Expression Profile; Genomics; Goals; 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; Pathway interactions; Patient Selection; Patients; Peptide Library; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phase Ib/II Clinical Trial; Population; Prediction of Response to Therapy; Public Health; Quality of life; Radiation; Recurrent tumor; Regimen; Relapse; Research; Resistance; 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; Urothelium; adaptive immune response; antigen-specific T cells; arm; biomarker signature; 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; participant enrollment; phase 3 study; phase III trial; phase change; point of care; point-of-care diagnostics; precision medicine; predictive signature; programmed cell death ligand 1; programmed cell death protein 1; prospective; recruit; relapse patients; response; safety assessment; standard care; targeted treatment; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor DNA; tumor immunology; tumor-immune system interactions

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.

项目摘要：每年有超过 81,000 名新患者被诊断患有尿路上皮癌 (UC) 膀胱炎，17,000 人将死于该病。大多数患有非肌肉侵袭性疾病 (NMIBC) 诊断时。尽管使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）注入膀胱后，三分之二的 NMIBC 患者会出现复发 BCG 治疗后的肿瘤。膀胱切除术虽然具有治愈作用，但与改变生活质量有关 在许多情况下，影响是不可行的，或者是被拒绝的。卡介苗复发 NMIBC 的非手术治疗选择 缺乏病人。在转移性 UC 中，观察到具有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。检验新颖的组合 将 CPI 纳入 BCG 复发 NMIBC 中是自然而然的下一步。在这个提案中，我们 计划定义安全性和临床活性，评估几种基因组的即时诊断潜力 生物标志物平台，并对 CPI 疗法的新型组合进行初步机制研究 在多臂、多阶段 ADAPT-BLADDER 1b/2 期临床试验中同时使用 BCG 和放射治疗， 长期目标是为未来改变实践的第三阶段试验的设计提供信息。 目标：1) 证明免疫治疗联合方案的安全性和临床疗效 BCG 复发性 NMIBC 患者； 2) 鉴定与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 既往 BCG 治疗后出现肿瘤； 3) 证明肿瘤抗原特异性 T 细胞反应的存在 将此类反应与 NMIBC 患者的新型免疫治疗方案的临床结果相关联 既往 BCG 治疗后肿瘤复发。 方法：我们将通过多中心 1 b / 2 期 ADAPT- 前瞻性评估每个目标 BLADDER 试验在超过 170 名 BCG 复发 NMIBC 患者中进行。具体来说，我们将记录安全性 每个方案在第 1 阶段和第 2 阶段的临床疗效。我们将关联基线和后期 具有临床益处的治疗基因组生物标志物特征。最后，我们还要考察一下人的能力。 个性化新抗原肽库以扩展抗原特异性 T 细胞克隆。 我们假设免疫治疗联合方案将是安全有效的。此外，我们 预测能够区分患者的护理点基因组生物标志物特征的识别 最有可能受益；我们期望识别出预测治疗的新基因表达特征 反应和抵抗；我们怀疑计划中的功能性肿瘤免疫学研究将 产生具有启发性的发现。