Andersson Y, Engebraaten O, Juell S, Aamdal S, Brunsvig P, Fodstad Ø, Dueland S
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.
Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway.
Br J Cancer. 2015 Dec 1;113(11):1548-55. doi: 10.1038/bjc.2015.380. Epub 2015 Nov 10.
A phase I trial was performed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics and immunogenicity of the anti-EpCAM immunotoxin (IT) MOC31PE in cancer patients. An important part of the study was to investigate whether the addition of Sandimmune (cyclosporin, CsA) suppressed the development of anti-IT antibodies.
Patients with EpCAM-positive metastatic disease were eligible for treatment with intravenous MOC31PE using a modified Fibonacci dose escalation sequence. Maximum tolerated dose was first established without, then with intravenously administered CsA.
Sixty-three patients were treated with MOC31PE in doses ranging from 0.5 to 8 μg kg(-1). Maximum tolerated dose was 8 μg kg(-1) for MOC31PE alone, and 6.5 μg kg(-1) when combined with CsA. The dose-limiting adverse event was reversible liver toxicity. No radiological complete or partial responses were observed, whereas stable disease was seen in 36% of the patients receiving MOC31PE only. The pharmacokinetic profile of MOC31PE was characterised by linear kinetics and with a half-life of ∼3 h. The addition of CsA delayed the generation of anti-IT antibodies.
Intravenous infusion of MOC31PE can safely be administered to cancer patients. Immune suppression with CsA delays the development of anti-MOC31PE antibodies. The antitumour effect of MOC31PE warrants further evaluation in EpCAM-positive metastatic disease.
进行了一项I期试验，以确定抗EpCAM免疫毒素（IT）MOC31PE在癌症患者中的最大耐受剂量（MTD）、安全性、药代动力学和免疫原性。该研究的一个重要部分是调查添加山地明（环孢素，CsA）是否能抑制抗IT抗体的产生。
EpCAM阳性转移性疾病患者符合使用改良的斐波那契剂量递增序列静脉注射MOC31PE进行治疗的条件。首先在不使用静脉注射CsA的情况下确定最大耐受剂量，然后再使用CsA确定最大耐受剂量。
63例患者接受了剂量范围为0.5至8μg kg⁻¹的MOC31PE治疗。MOC31PE单独使用时的最大耐受剂量为8μg kg⁻¹，与CsA联合使用时为6.5μg kg⁻¹。剂量限制性不良事件为可逆性肝毒性。未观察到放射学上的完全或部分缓解，而仅接受MOC31PE治疗的患者中有36%出现疾病稳定。MOC31PE的药代动力学特征为线性动力学，半衰期约为3小时。添加CsA可延迟抗IT抗体的产生。
静脉输注MOC31PE可安全地应用于癌症患者。用CsA进行免疫抑制可延迟抗MOC31PE抗体的产生。MOC31PE的抗肿瘤作用值得在EpCAM阳性转移性疾病中进一步评估。
