PHASE II MULTICENTER TRIAL OF 90 YTTRIUM DOTA BIOTIN IN SUBJECTS W/ CANCER

90 钇 DOTA 生物素在癌症受试者中的 II 期多中心试验

• 批准号: 6264323
• 负责人: Susan J. Knox
• 金额: $ 0.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6264323
• 关键词: antibody; biotin; clinical research; colon neoplasms; colorectal neoplasms; drug adverse effect; human subject; human therapy evaluation; immunoconjugates; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; yttrium

Colon cancer Study Results Antibody pretargeting is a novel strategy to enhance tumor-selective delivery of toxic agents by administering an antibody conjugate to target tumors, and then administering a toxic agent such as a radioisotope which selectively binds to the conjugate. We conducted a phase II multi-center study to evaluate the efficacy and safety of such an approach in patients with advanced colorectal carcinoma (CRC). 25 patients (13 male, 12 female) with metastatic CRC were enrolled, median age 55 (range 37-74). Tumors were pretargeted through administration of murine monoclonal antibody NR-LU-10/streptavidin conjugate, dosed to 125 mg/ml of patient plasma volume. 48 hours later biotin-galactose-human serum albumin clearing agent was given to bind circulating antibody through streptavidin-biotin interactions for clearance by the reticuloendothelial system. 24 hours after the clearing agent, a single 110 mCi/m2 dose of biotinylated 90 Yttrium-DOTA was administered by intravenous bolus injection to target tumor sites through streptavidin-biotin binding with NR-LU-10. Two patients (8%) had a >80% decrease in the sum of the products of sentinel lesion diameters. One grade 5 toxicity was seen due to severe diarrhea, inducing hypokalemia, which potentially contributed to a fatal cardiac arrythmia in a patient with underlying coronary artery disease. The most common grade 3-4 toxicities were diarrhea (28%), thrombocytopenia (28%), anemia (16%), neutropenia (16%), fatigue (16%), and hypokalemia (12%). The targeted toxicity of diarrhea was probably related to expression of gp40, the NR-LU-10 target, on normal colon. Pancytopenia resulted from non-targeted toxicity from circulating radioisotope, as NR-LU-10 does not bind to bone marrow cells. This study demonstrates that a pretargeting approach can deliver therapeutic doses of radioisotopes to tumor in some cases. While the degree of response to a single dose of 90Yttrium-DOTA in patients with advanced, refractory disease is modest, the significant toxicities seen in this study warrantt additional refinement of the pretargeting strategy. Prostate Cancer Study Results. The utility of radiolabeled monoclonal antibodies has been limited by inadequate localization of antibody in tumor sites, and the presence of non-specific binding, resulting in a narrow therapeutic index. In order to address this problem, 14 patients with HRPC were treated with PRit. Patients were pretreated with NR-LU-10, a pan-carcinoma specific antibody, linked to streptavidin. Forty-eight hours later any remaining (free) circulating antibody was cleared with biotinylated human albumin. All patients had their serum assayed for free antibody prior to receiving subsequent therapy. Twenty-four hours after the clearing agent, Yttrium-90-DOTA conjugated to biotin was administered in order to deliver a radiation dose to tumor-bound antibody. Two of 14 (14%) patients had a durable > 50% decline in PSA. Symptomatic improvement was observed in a majority of patients with pain. Toxicity was moderate, with grade > diarrhea occurring in 28% of patients, grade 4 neutropenia in 15%, and transient thrombocytopenia in 38%. The median time to Plt nadir was 5 weeks, and to ANC nadir 6.5 weeks. Human anti-mouse antibody and human anti-streptavidin antibody formation was universal. We conclude that PRit is feasible in patients with HPRC, and is able to safely deliver large doses of radiation targeted to tumor sites. This approach appears to have modest anti-HPRC activity, and future work will need to address anti-mouse and anti-streptavidin antibody formation.

结肠癌研究结果抗体预靶向是一种新的策略，通过施用抗体缀合物靶向肿瘤，然后施用毒性剂如选择性结合缀合物的放射性同位素，来增强毒性剂的肿瘤选择性递送。我们进行了一项II期多中心研究，以评估这种方法在晚期结直肠癌（CRC）患者中的疗效和安全性。入组了25例转移性CRC患者（13例男性，12例女性），中位年龄55岁（范围37-74）。通过施用鼠单克隆抗体NR-LU-10/链霉亲和素缀合物（剂量为125 mg/ml患者血浆体积）来预靶向肿瘤。48小时后，给予生物素-半乳糖-人血清白蛋白清除剂，以通过链霉亲和素-生物素相互作用结合循环抗体，从而通过网状内皮系统清除。在清除剂后24小时，通过静脉内推注将单次110 mCi/m2剂量的生物素化的90钇-DOTA施用至靶肿瘤部位，通过链霉亲和素-生物素与NR-LU-10结合。两名患者（8%）的前哨病变直径乘积之和减少>80%。由于重度腹泻，观察到1例5级毒性，诱导低钾血症，这可能导致1例基础冠状动脉疾病患者发生致死性心律失常。最常见的3-4级毒性为腹泻（28%）、血小板减少症（28%）、贫血（16%）、中性粒细胞减少症（16%）、疲乏（16%）和低钾血症（12%）。腹泻的靶向毒性可能与NR-LU-10靶点gp 40在正常结肠上的表达有关。全血细胞减少症由循环放射性同位素的非靶向毒性引起，因为NR-LU-10不与骨髓细胞结合。这项研究表明，在某些情况下，预靶向方法可以将治疗剂量的放射性同位素递送到肿瘤。虽然在晚期难治性疾病患者中对单剂量90钇-DOTA的反应程度是适度的，但在本研究中观察到的显著毒性不包括对预靶向策略的额外改进。前列腺癌的治疗方法放射性标记的单克隆抗体的效用受到肿瘤部位抗体定位不足和非特异性结合存在的限制，导致治疗指数狭窄。为了解决这个问题，14例HRPC患者接受了PRit治疗。患者用NR-LU-10预处理，NR-LU-10是一种与链霉亲和素连接的泛癌特异性抗体。48小时后，用生物素化人血白蛋白清除任何剩余（游离）循环抗体。所有患者在接受后续治疗前均进行血清游离抗体测定。在清除剂后24小时，施用与生物素缀合的钇-90-DOTA以将放射剂量递送至肿瘤结合的抗体。14例患者中有2例（14%）PSA持续下降> 50%。在大多数疼痛患者中观察到症状改善。毒性为中度，28%的患者发生>级腹泻，15%发生4级中性粒细胞减少，38%发生一过性血小板减少。至Plt最低点的中位时间为5周，至ANC最低点的中位时间为6.5周。人源抗鼠抗体和人源抗链霉亲和素抗体的形成具有普遍性。我们的结论是PRit在HPRC患者中是可行的，并且能够安全地向肿瘤部位提供大剂量的放射。这种方法似乎具有适度的抗HPRC活性，未来的工作将需要解决抗小鼠和抗链霉亲和素抗体的形成。