Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer
Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer
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DOI：
10.1200/jco.1996.14.6.1787
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发表时间：
1996-06-01
影响因子：
45.3
通讯作者：
Old, LJ
中科院分区：
文献类型：
--
作者：
Welt, S;Scott, AM;Old, LJ
目的：设计了一项I/II期研究，以确定碘125标记的单克隆抗体A33的最大耐受剂量（MTD（I-125-mAb A33）、其限制性器官毒性以及肿瘤病变中放射性的摄取和保留。用单剂量I-125-mAb A33治疗先前未接受过放疗的晚期化疗抗性结肠癌患者（N = 21）。I-125剂量从50 mCi/m2递增至350 mCi/m2，增量为50 mCi/m2。结果：20例有放射学证据的患者均显示I-125定位于病变部位。14例患者中有12例在抗体给药后4 - 6周接受了成像研究，肿瘤病变中有足够的同位素保留，可以进行外部成像。除1例既往暴露于丝裂霉素的患者发生一过性3级血小板减少症外，未观察到重大毒性。虽然同位素在正常肠道中显示出可变的摄取，但胃肠道症状轻微或不存在，并且在任何情况下粪便都没有变成愈创木酚阳性。I-125剂量高达350 mCi/m（2）时未达到MTD。然而，细胞毒性试验表明，接受最高剂量治疗的患者具有足够高的血清I-125-mAb A33水平，可在体外裂解结肠癌细胞。在21例患者中，1例患者的癌胚抗原（CEA）水平恢复正常，2例患者分别下降35%和23%;另外1例患者在计算机断层扫描上有混合反应。此外，在完成I-125-mAb A33研究后，在接受化疗（卡莫司汀[BCNU]、长春新碱、氟尿嘧啶和链脲佐菌素[BOF-Strep]）的患者中观察到了显著的反应。结论：低能量放射免疫治疗，剂量为VP至350 mCi/m2的I-125-mAb A33不会引起肠道或骨髓毒性。由于在研究剂量下锁定了毒性，因此在这些重度预治疗患者中的适度抗肿瘤活性令人鼓舞。肿瘤中的长放射性保留表明，基于计算的肿瘤相对于正常组织的剂量递送，具有长半衰期的同位素可能具有治疗优势。由于骨髓剂量低，需要进一步使用人源化mAb A33进行I-125试验，并且必须进行对照研究以评估放射免疫疗法和化学疗法的组合。(C)1996年，美国临床肿瘤学会。
Purpose: A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (I-125-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions.Patients and Methods: patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single I-125-mAb A33 dose. I-125 doses were escalated from 50 to 350 mCi/m(2) in 50-mCi/m(2) increments. Radioimmunoscintigrams were performed for up to 6 weeks after I-125-mAb A33 administration.Results: All 20 patients with radiologic evidence of disease showed localization of I-125 to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools become guaiac-positive. The MTD was not reached at I-125 doses up to 350 mCi/m(2). However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of I-125-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy (carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the I-125-mAb A33 study.Conclusion: Low-energy emission radioimmunotherapy with doses of vp to 350 mCi/m(2) of I-125-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lock of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further I-125 trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy. (C) 1996 by American Society of Clinical Oncology.