Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: Long-term outcome from the ImmunoPeCa phase I/II trial

Abstract Background. Peritoneal metastasis (PM) from colorectal cancer (CRC) is associated with poor outcome, but in patients with resectable disease long-term survival through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be achieved. The dual rationale for applying intraperitoneal therapy in PM-CRC is dose intensification because of the peritoneal-plasma barrier and the conception of PM as a localized disease within the peritoneal cavity. Outcome following CRS-HIPEC is however highly variable and most patients will experience disease recurrence, illustrating the need for improved treatment. MOC31PE immunotoxin, composed of the monoclonal antibody MOC31 and pseudomonas exotoxin A (PE), was developed by researchers at the Norwegian Radium Hospital to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule (EpCAM), which is highly expressed in CRC. In the ImmunoPeCa trial we investigated the use of intraperitoneal MOC31PE as a novel therapeutic principle to target PM-CRC. Methods. The ImmunoPeCa trial was a dose-escalating phase I trial to evaluate the safety and tolerability (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC. Overall survival (OS) and disease-free survival (DFS) were also examined (secondary endpoints). Fifteen patients received the study drug at four dose levels (2.5 (n=3), 5.0 (n=3), 7.5 (n=3) and 10 (n=6) µg kg). Additional 6 patients, constituting an expansion cohort, were treated on dose level 4 (10 µg/kg). Results. There was no major toxicity, and the maximum tolerated dose was not reached. The systemic drug exposure was low, and MOC31PE in peritoneal fluid samples retained cytotoxic capacity, suggesting that the drug is very stable under physiological conditions. With a median follow-up of 29 months (95% CI 22-35 months), the median OS was not reached and the estimated 3-year OS was 85%. Estimated median DFS was 20 months (95% CI 8-33 months) and the estimated 3-year DFS was 36%, with a median follow-up of 25 months (95% CI 19-31 months). Although very encouraging, the results may reflect the selection of the cohort, and investigation in a larger cohort would be necessary to study efficacy. Conclusions. Intraperitoneal, perioperative administration of MOC31PE was safe and well tolerated. The promising long-term outcome combined with the low systemic uptake and retained cytotoxic activity in peritoneal fluid samples support further clinical testing. Citation Format: Ida S. Froysnes, Yvonne Andersson, Stein Larsen, Ben Davidson, Janne-Merete T. Oien, Kari H. Olsen, Karl-Erik Giercksky, Lars Julsrud, Oystein Fodstad, Svein Dueland, Kjersti Flatmark. Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: Long-term outcome from the ImmunoPeCa phase I/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT094.