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，2010年在美国有超过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124I-cG250正电子发射断层扫描（ImmunoPET）作为舒尼替尼靶向药物治疗期间的药理学和预测性生物标志物。这是我们之前的R21分数的第15百分位的重新提交。我们主要基于Wilex III期临床试验的最新文献和数据，解决了审稿人的批评。我们建议在25例晚期或转移性透明细胞RCC患者中进行124I-cG250成像的单中心、开放标签、研究者发起的试点研究，这些患者计划接受舒尼替尼治疗临床适应症。在基线、治疗期间和随访期间，将评估124I-cG250影像学检查x 3与骨扫描、胸部、腹部和骨盆高分辨率全身CT扫描、RECIST 1.1版本、进展时间和生存期的预测反应能力。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改进靶向药物治疗的先驱。我们的核心假设是，在基线时，基于124I- cG250免疫pet检测透明细胞肾癌中CAIX抗原表达，与标准CT和骨扫描相比，将提供更好的单次测试分期；此外，与RECIST 1.1相比，免疫pet测量124I-cG250摄取的变化将提供更早、更准确的晚期转移性RCC治疗反应评估。该R21源于放射标记G250的诊断和治疗研究，在该研究中，我们和其他研究人员确定，在患有透明细胞肾癌的小鼠和患者中，体内靶向导致了异常的靶本底比和每克注射剂量%。基于这些知识，我们对124I-cG250进行了一项用于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，来改善人类的诊断。临床基本原理是非侵入性的，肾肿块的组织学特征，从而避免不必要的肾脏手术，因为这些手术可能会损害临床上已经受损的肾脏。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非常有效（Divgi等人：Lancet Oncol 2007；8:304-10）。随后，Wilex公司与IBA US合作，获得了该方法的许可，目前已经完成了124I-cG250的III期关键试验。研究结果目前正在美国食品和药物管理局进行审查。据我们所知，这是第一个在GMP条件下生产的正电子标记抗体，并向FDA提交了诊断性NDA。目前的建议是这些先前研究的合理延伸，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。