Frøysnes Ida S, Andersson Yvonne, Larsen Stein G, Davidson Ben, Øien Janne-Merete Torset, Olsen Kari Hauge, Giercksky Karl-Erik, Julsrud Lars, Fodstad Øystein, Dueland Svein, Flatmark Kjersti
Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Faculty of Medicine, University of Oslo, Oslo, Norway.
Ann Surg Oncol. 2017 Jul;24(7):1916-1922. doi: 10.1245/s10434-017-5814-6. Epub 2017 Feb 21.
MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC.
This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC.
No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies.
Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.
MOC31PE免疫毒素旨在快速杀死表达肿瘤相关上皮细胞粘附分子的细胞，该分子在结直肠癌中高度表达。尽管细胞减灭术（CRS）和腹腔内热灌注化疗（HIPEC）可为结直肠癌腹膜转移（PM-CRC）患者提供长期生存机会，但大多数患者会出现疾病复发，因此需要新的治疗选择。在此基础上，MOC31PE正被开发为一种针对PM-CRC的新型治疗原则。
这是一项剂量递增的I期试验，旨在评估在接受CRS-HIPEC联合丝裂霉素C治疗的PM-CRC患者中腹腔内给予MOC31PE后的安全性和毒性（主要终点）、药代动力学特征以及中和抗体反应（次要终点）。15名患者在四个剂量水平（3+3+3+6）接受研究药物，在CRS-HIPEC后一天作为单剂量腹腔内给药。
未观察到剂量限制性毒性，且未达到最大耐受剂量。研究药物的全身吸收可忽略不计。腹腔液样本中的药物浓度处于细胞毒性范围内，并呈剂量依赖性增加。从腹腔中回收的MOC31PE在基于细胞的试验中保留了其细胞毒性活性。所有患者均产生了中和抗体。
腹腔内给予MOC31PE安全且耐受性良好，且全身摄取较低，MOC31PE似乎是局部腹腔内治疗的理想选择。该药物将在正在进行的II期扩展队列中进一步评估。
