Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the ImmunoPeCa Phase 1 Trial

Abstract

Peritoneal metastasis (PM) is an important feature of epithelial ovarian cancer (EOC) and is a frequent site of drug resistant disease recurrence, identifying PM-EOC an important clinical challenge. The MOC31PE immunotoxin targets and kills tumor cells expressing the epithelial cell adhesion molecule (EpCAM), which is highly expressed in EOC, and MOC31PE is being investigated for use in treatment of PM-EOC. The efficacy of MOC31PE treatment alone and in combination with cytotoxic drugs was investigated in two human EpCAM expressing EOC cell lines, B76 and MDHA-2774, in vitro and in corresponding mouse models mimicking PM-EOC. MOC31PE efficaciously killed tumor cells alone and showed equal or superior activity in vitro (paclitaxel, cisplatin, carboplatin) and in vivo (paclitaxel, mitomycin C) compared to the investigated cytotoxic drugs. Additive, or importantly, no antagonistic effects were observed in combination experiments. In ex vivo cell culture, the cytotoxic effect of MOC31PE was studied on freshly isolated surgical EOC samples. All investigated fresh EOC samples expressed EpCAM and MOC31PE effectively reduced cell viability in ex vivo cultures. In conclusion, these results, together with our previous preclinical and clinical experience, support development of MOC31PE for treatment of PM-EOC in combination with currently used cytotoxic drugs.

Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years?

“…MT110 (solitomab) is a tandem single-chain antibody construct comprised of an EpCAM-and CD3-specific binding domain developed by Micromet Inc. [117]. Pharmacokinetics, tolerability, safety, and anti-tumor activity of MT110 were assessed in a dose-escalating phase I clinical trial in metastatic colorectal, gastric, and lung carcinomas (129) with disease stabilization in 7/19 patients. Due to gastrointestinal toxicities, solitomab could not be escalated to more efficacious dose levels, and the program was abandoned.…”

“…Subsequently, MOC31PE was applied to address peritoneal metastasis in colorectal and ovarian cancers within the ImmunoPeCa phase I/II. Based on the promising cytotoxicity profile and a low systemic uptake, MOC31PE is currently further evaluated in a clinical phase II study [128,129].…”

ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis

“…This was an open, dose-finding trial (NCT00769405) primarily investigating safety and toxicity upon intraperitoneal MOC31PE administration the day after CRS-HIPEC for PM-CRC [15]. Pharmacokinetic profile, neutralizing anti-immunotoxin antibody response, overall survival (OS), and disease-free survival (DFS) were secondary endpoints.…”

“…Pharmacokinetic profile, neutralizing anti-immunotoxin antibody response, overall survival (OS), and disease-free survival (DFS) were secondary endpoints. Safety, toxicity, pharmacokinetics and neutralizing antibody response for the first 15 patients were presented before [15]. The study was carried out at The Norwegian Radium Hospital, Oslo University Hospital (Comprehensive Cancer Center), between September 2014 and September 2016.…”

“…We have previously shown that the drug was safe and well tolerated, that peritoneal fluid samples had high drug concentrations, that MOC31PE was still cytotoxic after peritoneal exposure, and that systemic drug uptake was low, in the first 15 patients of the ImmunoPeCa trial [15]. We established a dose level for further investigation in an expansion cohort of 6 patients and concluded that MOC31PE seemed ideally suited for local treatment in the peritoneal cavity.…”