Dose escalation and dosimetry of first-in-human α radioimmunotherapy with 212Pb-TCMC-trastuzumab.
Dose escalation and dosimetry of first-in-human α radioimmunotherapy with 212Pb-TCMC-trastuzumab.
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DOI：
10.2967/jnumed.114.143842
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
Straughn JM Jr
中科院分区：
文献类型：
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作者：
Meredith R;Torgue J;Shen S;Fisher DR;Banaga E;Bunch P;Morgan D;Fan J;Straughn JM Jr
我们的目的是研究腹腔注射（IP）212 Pb-TCMC-曲妥珠单抗（TCMC是S-2-（4-异硫氰基苯甲基）-1，4，7，10-四氮杂-1，4，7，10=四（2-氨基甲酰基甲基）环十二烷）在HER-2表达的恶性肿瘤患者中的安全性、分布、药代动力学、免疫原性和肿瘤反应。在标准的3+3 I期剂量递增设计中，212 Pb-TCMC-曲妥珠单抗在标准治疗失败的腹膜癌病患者接受4 mg/kg IV曲妥珠单抗后4小时内IP给药。五个剂量水平（7.4、9.6、12.6、16.3、21.1 MBq/m2）在第一组>1年和其他组>4个月时显示出最小毒性。无实质性毒性与剂量测定评估一致（骨髓平均等效剂量= 0.18 mSv/MBq）。使用初始队列（n=3）中获得的药代动力学数据进行辐射剂量测定评估。放射性从腹膜腔到循环血液的再分布有限，通过尿液排泄清除，24小时内未观察到主要器官的特异性摄取。放射性标记抗体的最大血清浓度在24 h（衰减校正至进样时间）和500 Bq/mL（衰减校正至采集时间）时为22.9%。24小时内非衰变校正的累积尿排泄≤6%（2.3个半衰期）。在最新的队列中，在距离患者1 m处进行的剂量率测量记录不到5μSv/hr（使用便携式探测器），显著低于使用核医学成像剂通常观察到的剂量率。对前4个队列的血清进行的抗药抗体测定均为阴性。腹膜癌转移患者IP 212 Pb-TCMC-曲妥珠单抗治疗的5个剂量水平显示几乎没有药物相关毒性，与剂量测定计算一致。
Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity and tumor response of intraperitoneal (IP) 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyantobenzl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10=tetra (2-carbamoylmethl) cyclododecane) in patients with HER-2 expressing malignancy. In a standard 3+3 Phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered IP less than 4 hours after giving 4mg/kg IV trastuzumab to patients with peritoneal carcinomatosis who had failed standard therapies. Five dosage levels (7.4, 9.6, 12.6, 16.3, 21.1 MBq/m2) showed minimal toxicity at >1 year for the first group and >4 months for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow = 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n=3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion and no specific uptake in major organs was observed in 24 hours. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24h (decay corrected to injection time) and 500 Bq/mL (decay corrected to collection time). Non-decay corrected cumulative urinary excretion was ≤6% in 24h (2.3 half lives). Dose rate measurements performed at 1m from the patient registered less than 5μSv/hr (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Anti-drug antibody assays performed on serum from the first 4 cohorts were all negative. Five dose levels of IP 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent related toxicity, consistent with the dosimetry calculations.