124I-cG250 ImmunoPET Imaging of Sunitinib Treatment Response in Renal Cell Cancer

肾细胞癌舒尼替尼治疗反应的 124I-cG250 免疫 PET 成像

• 批准号: 8257032
• 负责人: Steven Mark Larson
• 金额: $ 37.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257032
• 关键词: Abdomen; Accounting; Address; Adverse effects; Antibodies; Antibody Affinity; Antigens; Applications Grants; Benign; Binding; Biological Markers; Cancer Detection; Cessation of life; Characteristics; Chest; Clear Cell; Clinical; Clinical Protocols; Clinical Trials; Clinical Trials Design; Collaborations; Conduct Clinical Trials; Critiques; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Dilatation - action; Dose; Ensure; Evaluation; Failure; Genitourinary system; Growth; Histology; Image; Imaging Techniques; Individual; Inflammation; Kidney; Knowledge; Label; Lead; Lesion; Letters; Licensing; Literature; Malignant Neoplasms; Measures; Medical Oncologist; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Lung; Metastatic Renal Cell Cancer; Methodology; Monitor; Mus; Neck; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient Selection; Patients; Peer Review; Pelvis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Pilot Projects; Positron; Positron-Emission Tomography; Protocols documentation; Radiolabeled; Reagent; Regimen; Renal Cell Carcinoma; Renal Mass; Renal carcinoma; Research Personnel; Resistance; Resolution; Safety; Schedule; Signal Transduction; Staging; Systemic Therapy; Testing; Therapeutic Studies; Time; Tissues; Toxic effect; Treatment Protocols; United States; Urinary tract; Urogenital Cancer; X-Ray Computed Tomography; base; bone imaging; cancer diagnosis; carbonate dehydratase; effective therapy; experience; follow-up; imaging modality; improved; in vivo; man; molecular imaging; novel; novel therapeutics; open label; phase 1 study; radiotracer; response; soft tissue; standard of care; therapy resistant; treatment planning; treatment response; tumor; uptake

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is the most common malignancy of the kidney, accounting for more than 58,000 new diagnoses of cancer and 13,000 cancer deaths in the United States during 2010. The central theme of this R21 (PAR 08-147) is to refine the current use of Positron Emission Tomography of 124I-cG250 (ImmunoPET) in RCC as a pharmacodynamic and predictive biomarker during sunitinib targeted drug therapy. This is a resubmission of our prior R21 scored at the 15th percentile. We have addressed the reviewer's critique, based primarily on newly available literature and data from the Phase III Wilex trial. We propose a single center, open-label, investigator-initiated, pilot study of 124I-cG250 imaging in 25 patients with advanced or metastatic clear cell RCC who are scheduled to receive treatment with sunitinib for clinical indications. The 124I-cG250 imaging test x 3 at baseline, during treatment and in follow-up, will be assessed for its ability to predict response i comparison to bone scan, high resolution body CT scan of the chest, abdomen, and pelvis, RECIST version 1.1, time to progression and survival. The trial will be performed in collaboration with Dr. Robert Motzer, Genitourinary medical oncologist, who has pioneered improved targeted drug therapies for RCC. Our core hypothesis is that at baseline, detection of CAIX antigen expression in clear cell renal cancer, based on 124I- cG250 ImmunoPET, will provide improved single test staging in comparison to standard CT and bone scan; Also, ImmunoPET measured changes in 124I-cG250 uptake will provide earlier and more accurate assessment of treatment response in advanced metastatic RCC, in comparison to RECIST 1.1. This R21 grew out of diagnostic and therapeutic studies with radiolabeled G250, in which we and others determined that in vivo targeting in mice and patients bearing clear cell renal cancer resulted in exceptional target to background ratios and % injected dose per gram. Based on this knowledge, we performed a Phase I study with 124I-cG250 for detection of clear-cell renal cancer, hoping to exploit the combination of an exceptional targeting antibody, and the sensitivity and quantitative power of PET imaging, for improved diagnosis in man. The clinical rationale was to characterize non-invasively, the histology of a renal mass and therefore avoid unnecessary renal surgery that could potentially damage kidneys that are often already clinically compromised. The phase I study found the PET imaging approach to be highly effective for the non-invasive diagnosis of clear cell renal cancer (Divgi et al: Lancet Oncol 2007;8:304-10). Subsequently, Wilex Inc, in partnership with IBA US, licensed the approach and has now completed a Phase III pivotal trial with 124I-cG250. Study results are now with the FDA for review. As far as we are aware, this is the first positron labeled antibody that has been manufactured under GMP conditions and submitted for a diagnostic NDA from the FDA. The current proposal is a logical extension of these prior studies and, if successful, will improve staging and monitoring of systemic treatment response in advanced renal cell carcinoma. PUBLIC HEALTH RELEVANCE: In 2010, 13,000 US patients will die of advanced Renal Cancer. Recently, promising new drugs that block growth signals responsible for proliferation (sunitinib) have been developed, but these agents are only effective in 50% of the patients, and those who do not respond may experience unpleasant side-effects. Positron Emission Tomography based molecular imaging using 124I-cG250 ImmunoPET will help select individual patients who will respond to these drugs and improve individual patient management.

描述（由申请人提供）：肾细胞癌（RCC）是最常见的肾脏恶性肿瘤，在2010年期间，美国有超过58，000例新诊断的癌症和13，000例癌症死亡。本R21（PAR 08-147）的中心主题是完善目前在RCC中使用的124 I-cG 250（ImmunoPET）正电子发射断层扫描，作为舒尼替尼靶向药物治疗期间的药效学和预测性生物标志物。这是我们之前R21评分为第15百分位的重新提交。我们已经解决了评论家的批评，主要是基于新获得的文献和III期Wilex试验的数据。我们提出了一个单中心，开放标签，闪烁器启动，124 I-cG 250成像在25例晚期或转移性透明细胞肾细胞癌患者谁预定接受舒尼替尼治疗的临床适应症的初步研究。将评估基线、治疗期间和随访时的124 I-cG 250成像检查x 3与骨扫描、胸部、腹部和骨盆的高分辨率身体CT扫描（RECIST版本1.1）、至进展时间和生存期相比预测缓解的能力。该试验将与泌尿生殖医学肿瘤学家Robert Motzer博士合作进行，他是RCC靶向药物治疗的先驱。我们的核心假设是，在基线时，基于124 I-cG 250 ImmunoPET检测透明细胞肾癌中的CAIX抗原表达，与标准CT和骨扫描相比，将提供改善的单次测试分期;此外，与RECIST 1.1相比，ImmunoPET测量的124 I-cG 250摄取变化将提供晚期转移性RCC中治疗反应的更早和更准确的评估。这种R21源于放射性标记的G250的诊断和治疗研究，在这些研究中，我们和其他人确定，在小鼠和患有透明细胞肾癌的患者中的体内靶向导致异常的靶与背景比和每克注射剂量%。基于这些知识，我们进行了一项使用124 I-cG 250检测透明细胞肾癌的I期研究，希望利用一种特殊的靶向抗体，以及PET成像的灵敏度和定量能力的组合，用于改善人类的诊断。临床原理是非侵入性地表征肾脏肿块的组织学，从而避免不必要的肾脏手术，这些手术可能会损害临床上通常已经受损的肾脏。I期研究发现PET成像方法对于透明细胞肾癌的非侵入性诊断是高度有效的（Divgi等人：Lancet Oncol 2007;8：304-10）。随后，Wilex Inc与IBA US合作，批准了该方法，现在已经完成了124 I-cG 250的III期关键试验。研究结果目前正在FDA进行审查。据我们所知，这是第一个正电子标记的抗体，已在GMP条件下生产，并提交给FDA的诊断NDA。目前的建议是这些先前研究的逻辑延伸，如果成功，将改善晚期肾细胞癌的分期和全身治疗反应的监测。 公共卫生相关性：2010年，13，000名美国患者将死于晚期肾癌。最近，已经开发出了阻断负责增殖的生长信号的有前途的新药（舒尼替尼），但这些药物仅对50%的患者有效，并且那些没有反应的患者可能会经历令人不快的副作用。使用124 I-cG 250 ImmunoPET的基于正电子发射断层扫描的分子成像将有助于选择对这些药物有反应的个体患者，并改善个体患者的管理。