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: 8338883
• 负责人: Steven Mark Larson
• 金额: $ 37.95万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338883
• 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.

说明（由申请人提供）：肾细胞癌 (RCC) 是最常见的肾脏恶性肿瘤，2010 年美国新诊断出 58,000 多例癌症，并导致 13,000 例癌症死亡。该 R21 (PAR 08-147) 的中心主题是改进 124I-cG250 (ImmunoPET) 正电子发射断层扫描的当前使用情况。 RCC 作为药效学和预测 舒尼替尼靶向药物治疗期间的生物标志物。这是我们之前 R21 得分为第 15 个百分点的重新提交。我们主要根据新获得的文献和 III 期 Wilex 试验的数据，解决了审稿人的批评。我们提议对 25 名晚期或转移性透明细胞 RCC 患者进行一项单中心、开放标签、由研究者发起的 124I-cG250 成像试点研究，这些患者计划因临床适应症接受舒尼替尼治疗。将在基线、治疗期间和随访期间评估 124I-cG250 成像测试 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、进展时间和生存时间的比较，评估其预测反应的能力。该试验将与泌尿生殖肿瘤医学专家 Robert Motzer 博士合作进行，Robert Motzer 博士是肾细胞癌靶向药物改良疗法的先驱。我们的核心假设是，在基线时，与标准 CT 和骨扫描相比，基于 124I-cG250 免疫 PET 检测透明细胞肾癌中 CAIX 抗原表达将提供改进的单次测试分期；此外，与 RECIST 1.1 相比，ImmunoPET 测量的 124I-cG250 摄取变化将为晚期转移性肾细胞癌的治疗反应提供更早、更准确的评估。该 R21 源于放射性标记 G250 的诊断和治疗研究，在这些研究中，我们和其他人确定，对患有透明细胞肾癌的小鼠和患者进行体内靶向导致了异常的靶标与背景比率和每克注射剂量百分比。基于这些知识，我们使用 124I-cG250 进行了一项用于检测透明细胞肾癌的 I 期研究，希望利用特殊的靶向抗体与 PET 成像的灵敏度和定量能力的组合来改善人类的诊断。临床原理是非侵入性地表征肾脏肿块的组织学特征，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非常有效（Divgi 等人：Lancet Oncol 2007；8：304-10）。随后，Wilex Inc 与 IBA US 合作，获得了该方法的许可，现已完成 124I-cG250 的 III 期关键试验。研究结果现已提交 FDA 审查。据我们所知，这是第一个在 GMP 条件下生产并提交 FDA 诊断新药申请的正电子标记抗体。目前的提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全身治疗反应的分期和监测。