Targeting the MET Pathway in Urothelial Carcinoma

靶向尿路上皮癌的 MET 通路

• 批准号: 10014737
• 负责人: Andrea Apolo
• 金额: $ 70.49万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014737
• 关键词: Abdomen; Address; Aftercare; Anchorage-Independent Growth; Archives; Biopsy; Bladder; Blood; Cancer Therapy Evaluation Program; Cell Extracts; Chemotherapy-Oncologic Procedure; Chest; Chimeric Proteins; Cisplatin; Clinical; Clinical Trials; Cytotoxic Chemotherapy; DNA analysis; Development; Diagnosis; Disease; Disease Progression; Dose; Enrollment; Evaluable Disease; Evaluation; FLT3 gene; Formalin; Freezing; Genes; Genomic DNA; Goals; Growth; Immunoassay; Institutional Review Boards; KDR gene; Lead; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measurement; Mediator of activation protein; Neoplasm Metastasis; Oral; Outcome; PGF gene; PIK3CA gene; PTEN gene; Paraffin; Paraffin Embedding; Pathway interactions; Patient-Focused Outcomes; Patients; Pelvis; Plasma; Play; Primary Neoplasm; Prior Chemotherapy; Prognostic Factor; Prognostic Marker; Progression-Free Survivals; Protein Tyrosine Kinase; Proteins; Protocols documentation; Radiology Specialty; Reader; Receptor Protein-Tyrosine Kinases; Recombinants; Reference Standards; Refractory; Renal pelvis; Role; Sampling; Signal Transduction; Site; Slide; Source; System; Systemic Therapy; Testing; Time; Time Study; Tissues; Toxic effect; Transitional Cell Carcinoma; Tumor Tissue; Tyrosine Kinase Inhibitor; Ureter Carcinoma; Urethral Cancer; Urine; Vascular Endothelial Growth Factors; X-Ray Computed Tomography; base; bladder transitional cell carcinoma; bone; cancer cell; chemotherapy; cohort; design; improved; improved outcome; inhibitor/antagonist; methionylmethionine; objective response rate; open label; overexpression; phase 2 study; phase II trial; predictive marker; protein expression; radiologist; receptor; research and development; response; response biomarker; targeted treatment; therapeutic target; tumor; tumorigenesis; urinary

Specific Aim 1: To improve the understanding of the role of the MET pathway in patients with advanced urothelial carcinoma Tumor Tissue MET expression: To describe the percentage of HGF and MET overexpression in urothelial tumors: [1] Formalin-fixed paraffin-embedded (FFPE) primary tumor samples from previously treated patients on other protocols (n=68) and primary tumors from cabozantinib study patients (n=55) will be analyzed for MET and HGF expression by IHC. Pre-cabozantinib treatment tumor biopsies of metastatic sites will also be obtained (so far 50% of patients agreed to a biopsy) and baseline MET and HGF expression of primary and metastatic tumor sites of these patients will be compared. Post treatment biopsies will be performed on a voluntary basis, to enable pre versus post comparisons of MET and HGF levels. [2] In fresh frozen tissue (FFT), HGF, MET, phosphoMET, RET, KIT, AXL and FLT3 will be quantitatively analyzed using a two-site electrochemiluminescent immunoassay developed for use with a Meso Scale Discovery (MSD) SectorImager 2400 plate reader in tumor samples from previously treated patients at the NCI (n=20) and at baseline from patients on study with cabozantinib (n=25). Use of a purified recombinant MET ectodomain-Ig fusion protein (358-MT, R&D Systems) as a reference standard permits quantitation as MET mass per mass total extracted cell protein. HGF, RET, KIT, AXL and FLT3 proteins will be quantitated similarly. Post treatment biopsies will be performed on a voluntary basis, and HGF, MET, phosphoMet, RET, KIT, AXL and FLT3 expression levels will be compared to baseline measurements. MET and HGF expression by IHC will be compared to MET, phosphoMET, and HGF expression by quantitative two-site electrochemiluminescent immunoassay. Results will be correlated with baseline prognostic factors such as tumor grade, stage, size, sites of metastatic disease, response to prior cisplatin therapy, response to cabozantinib, progression free survival and overall survival. Plasma MET expression: To determine whether plasma HGF, MET, VEGF-A, sVEGFR2 and PlGF levels analyzed by electrochemiluminescent immunoassay at baseline and after cabozantinib treatment are prognostic and/or predictive biomarkers of response to systemic therapy. Results will be correlated with baseline prognostic factors, response to cabozantinib, progression free survival and overall survival. Urine MET expression: To determine whether urinary HGF and soluble MET receptor (sMET) at baseline and after cabozantinib treatment are prognostic and/or predictive biomarkers of response to systemic therapy. Results will be correlated with baseline prognostic factors, source of urine (intact bladder, conduit, neobladder or nephrostomy), response to cabozantinib, progression free survival and overall survival. Genomic DNA analysis: Genes that are important downstream effectors of several tyrosine kinases involved in urothelial cancer and cabozantinib's targets will be analyzed and correlated with response. Genomic DNA will be prepared from FFPE. Tumor samples will be analyzed for MET, MET amplification, RET, PTEN, PIK3CA, and PIK3R1. AIM 2: To improve the outcome of patients with advanced urothelial carcinoma through the use of cabozantinib, a multi-receptor tyrosine kinase, primarily targeting MET and VEGFR2. A Phase II Study of Cabozantinib in Patients with Advanced/Metastatic Urothelial Carcinoma: we will formally test the hypothesis that cabozantinib, an oral dual-receptor tyrosine kinase inhibitor of MET and VEGFR2, improves the objective response rate in the second-line setting by 50-100%, i.e. from 10-15% (consistently observed with conventional chemotherapy) to at least 20%. We will also assess progression-free and overall survival. This open label, non-randomized, phase II trial of cabozantinib, 60 mg/day has been approved by CTEP and the NCI IRB (NCT01688999). Each patient will undergo response evaluation assessments with a CT scan of the chest, abdomen and pelvis at baseline and every 8 weeks (2 cycles) using RECIST 1.1 criteria by a central reference radiologist. Patients will remain on study until the time of disease progression or the development of unacceptable toxicity that is not manageable with dose reduction. Eligible patients must have a diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis, and must have received at least one prior cytotoxic chemotherapy regimen. Patient must be able to provide either archival tumor samples (H&E slides and one paraffin block or 10 unstained slides) and/or undergo tumor biopsy in order to enroll on study. The study follows an optimal two-stage design, in order to rule out an unacceptably low 5% overall response rate (ORR; p0=0.05), in favor of a modest response rate of 20% (p1=0.20). With alpha=0.05 and beta = 0.10, the study will initially enroll 21 evaluable patients and if 0 to 1 of the 21 respond by RECIST version 1.1, then no further patients will be accrued. If 2 or more of the first 21 respond, then accrual would continue. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer). The remainder will be enrolled on exploratory cohorts 2 & 3, bone only metastatic urothelial disease and non TCC bladder cancer, respectively, during the time the study is accruing patients to cohort 1.

具体目的1：提高对MET途径在晚期尿路癌肿瘤组织患者中的作用的了解：描述尿路上皮肿瘤中HGF和MET过表达的百分比：[1] [1]孔蛋白 - 拟合石蜡膜的孔状石蜡（FFPE）（FFPE）（FFPE）的原发性肿瘤（FFPE）在其他方案中的患者（n = 55）（N = 68）（N = 68）（N = 68）（N = 68）（N = 68）。通过IHC分析MET和HGF表达。还将比较这些患者的原发性和转移性肿瘤部位的基线MET和HGF表达转移性部位的前替尼治疗肿瘤活检（到目前为止50％的患者）。治疗后的活检将在自愿的基础上进行，以实现在MET和HGF水平的比较前与之后的比较。 [2]在新鲜的冷冻组织（FFT）中，将使用二点电化学的免疫测定法进行定量分析，以定量分析，用于与以前的tumor consection（MSD）Sectorimager 2400 Player（MSD）读取的患者（NC）（NC）患者（nc）患者（MSD）读取者（MSD）读取者（MSD）读取者（NC）（NC）（NC）中的NC = NC = NC的患者（ cabozantinib（n = 25）。使用纯化的重组元组蛋白蛋白融合蛋白（358-MT，R＆D系统）作为参考标准，可以定量定量为每质量总萃取的细胞蛋白。 HGF，RET，试剂盒，AXL和FLT3蛋白将被类似地定量。治疗后活检将在自愿的基础上进行，HGF，MET，磷酸盐，RET，KIT，AXL，AXL和FLT3表达水平将与基线测量值进行比较。 IHC通过定量的两个位点电化学免疫测定法比较IHC的MET和HGF表达。结果将与基线预后因素相关，例如肿瘤等级，阶段，大小，转移性疾病的部位，对先前的顺铂治疗的反应，对Cabozantinib的反应，无进展生存和整体存活率。血浆MET表达：确定血浆HGF，MET，VEGF-A，SVEGFR2和PLGF水平是否通过基线时电化学发光免疫测定和Cabozantinib治疗后是否是预后和/或预测性生物标志物对全身治疗的反应。结果将与基线预后因素，对Cabozantinib的反应，无进展生存和整体存活相关。尿液表达：确定基线时尿HGF和可溶性MET受体（SMET）以及Cabozantinib治疗后是否是对系统治疗反应的预后和/或预测性生物标志物。结果将与基线预后因素，尿液的来源（完整的膀胱，导管，新叶片或肾造口术）相关，对Cabozantinib的反应，无进展生存和整体存活。基因组DNA分析：将分析与尿路上皮癌和Cabozantinib靶标有关的几种酪氨酸激酶的重要下游效应子的基因，并与反应相关。基因组DNA将从FFPE制备。将分析肿瘤样品的MET，MET扩增，RET，PTEN，PIK3CA和PIK3R1。 AIM 2：通过使用Cabozantinib（一种多受体酪氨酸激酶），主要靶向MET和VEGFR2，可以改善晚期尿路上皮癌患者的结果。 Cabozantinib对患有晚期/转移性尿馆癌症患者的II期研究：我们将正式检验以下假设：Met和VegFR2的口服双受体酪氨酸激酶抑制剂Cabozantinib在二线环境中的客观响应率提高了50-100％，即在10-15％的惯例上（一致性地），将客观响应率提高了10-100％（一致），以提高（一致）。我们还将评估无进展和整体生存。 Cabozantinib的这款开放标签，非随机的II期试验，CTEP和NCI IRB（NCT01688999）批准了60 mg/天。每个患者将使用中央参考放射科医生使用Recist 1.1标准进行每8周（2个周期）的胸部，腹部和骨盆的CT扫描进行反应评估。患者将继续进行研究，直到疾病进展或不可接受的毒性产生，而剂量降低是无法控制的。合格的患者必须诊断出膀胱，尿道，输尿管或肾脏骨盆的转移性，进行性尿路上皮癌，并且必须至少接受过一种先前的细胞毒性化学疗法治疗方案。患者必须能够提供档案肿瘤样品（H＆E载玻片和1个石蜡块或10张未染色的载玻片）和/或进行肿瘤活检以进行研究。该研究遵循最佳的两阶段设计，以排除不可接受的低5％总反应率（ORR； P0 = 0.05），有利于适度的响应率为20％（p1 = 0.20）。在α= 0.05和β= 0.10的情况下，该研究最初将招募21名可评估患者，如果21次通过Recist版本1.1响应，则将不再累积患者。如果前21个反应中有2个或更多，那么应计。最多将注册55名受试者。多达45例患者将被累积到1（转移性，进行性尿路上皮癌）。其余的将纳入探索性队列2和3，在研究期间，分别仅骨转移性尿路上皮疾病和非TCC膀胱癌纳入了研究患者1。