Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial.
Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial.
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DOI：
10.1158/1078-0432.ccr-10-2579
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发表时间：
2011-06-15
期刊：
影响因子：
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通讯作者：
Goldenberg DM
中科院分区：
文献类型：
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作者：
Gulec SA;Cohen SJ;Pennington KL;Zuckier LS;Hauke RJ;Horne H;Wegener WA;Teoh N;Gold DV;Sharkey RM;Goldenberg DM
人源化抗体hPAM4特异性结合胰腺腺癌中表达的粘蛋白糖蛋白。这项I期研究评估了90Y-clivatuzumab tetraxetan （90y标记的hPAM4）在晚期胰腺癌患者中的单剂量治疗。21例患者（4例III期，17例IV期）在90Y-hPAM4之前接受111In-hPAM4成像和血清取样。研究程序评估了不良事件、安全实验室、计算机断层扫描（CT）、生物标志物、药代动力学、辐射剂量学和免疫原性（哈哈）。在12例患者中，in - hpam4显示出正常的生物分布，对红骨髓和实体器官的辐射剂量估计可接受放射免疫治疗和肿瘤靶向。1例患者在90Y-hPAM4前退出；另有20例患者接受90Y剂量，分别为15 （n = 7）、20 （n = 9）和25 mCi/m2 （n = 4）。治疗耐受性良好；唯一显著的药物相关毒性为（NCI CTC v.3） 3 ~ 4级中性粒细胞减少和血小板减少，随剂量增加而增加。无出血事件或严重感染，大多数血细胞减少症在12周内恢复到1级。3名患者在25 mCi/m2剂量下出现剂量限制性毒性，伴有4级细胞减少超过7天，从而确定20 mCi/m2为90Y的最大耐受剂量。2例患者出现临床意义不明的哈哈。大多数患者进展迅速，CA19-9水平在治疗1个月内升高，但7例患者在1.5至5.6个月的CT检查中无进展，其中3例获得短暂部分缓解（肿瘤直径缩小32%-52%）。90Y- clivatuzumab tetraxetan耐受性良好，在最大耐受90Y剂量下具有可控的血液学毒性，是晚期胰腺癌的潜在新疗法。
Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%–52% tumor diameter shrinkage). 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer.