'Trifunctional antibody' given via intraperitoneal infusions

ORLANDO—A team of European investigators is taking a novel immunotherapeutic approach to advanced gastrointestinal tract tumors using the “trifunctional antibody” catumaxomab (see box below).

A series of intraperitoneal infusions of this biologic agent appears not only to eradicate tumor cells and prolong progression-free survival, but also to effectively treat malignant ascites. Michael Ströhlein, MD, a surgical oncologist at the Merheim Medical Center Cologne, University of Witten/Herdecke, Germany, presented the findings at the 2008 Gastrointestinal Cancers Symposium (abstract 120).

Two studies presented

Two studies were presented at the meeting, one in patients with advanced gastric, colon, and pancreatic cancer, which evaluated tumor kill and clinical outcomes, and the other in epithelial cancer patients with malignant ascites, which evaluated clinical outcomes and the time to next therapeutic paracentesis.

The drug is first delivered intraoperatively just after tumor resection, with four subsequent infusions given in a dose- escalated fashion over 16 days.

“The concept is to take out the tumor with a curative resection, then attack the residual tumor cells inside the peritoneal cavity. This is a completely new approach,” said Dr. Ströhlein, who has performed this procedure on more than 100 patients.

In a phase I pilot study, 12 patients with advanced EpCAM+ gastrointestinal tumors (8 gastric, 3 pancreatic, 1 colon) were given catumaxomab intraoperatively in doses up to 20 µg, and postoperatively by 6-hour intraperitoneal infusion in doses of 10, 20, 50, and 150 µg.

Within 24 hours of the initial intraoperative treatment, immunocytochemical anti-cytokeratin staining of tumor cells in the lavage samples showed a significant decrease in tumor in five of eight patients, Dr. Ströhlein reported.

During follow-up, all treated patients were free of intra-abdominal tumor recurrence at a mean follow-up of 14.3 months. Two patients with pancreatic cancer died after progression of distant metastases, and two patients died from non-cancer-related causes. Excluding these four patients, survival times have ranged from 12+ to 25+ months.

“This is very interesting, because this is a group of patients in whom you would expect peritoneal carcinomatosis,” he pointed out.

Malignant ascites

At the meeting (abstract 106), Simon Parsons, DM, of the Department of Surgery, Nottingham University Hospitals, Nottingham, United Kingdom, described the open-label randomized phase II/III study in 129 patients with malignant ascites and EpCAM+ tumor cells due to nonovarian cancer (ovarian cancer patients were studied separately).

Patients had symptomatic ascites and at least one previous therapeutic ascites puncture within 5 weeks prior to screening. The median time since the last puncture was 14 days in the experimental arm and 17.5 days in the control arm.

Patients were randomized to treatment with paracentesis followed by intraperitoneal infusion of catumaxomab in doses of 10, 20, 40, or 150 µg on days 0, 3, 7, and 10 (n = 85) or to paracentesis alone (n = 44). The primary endpoint was puncture-free survival, ie, the time to first need for paracentesis after treatment or time to death, whichever occurred first.

Puncture-free survival was significantly longer in patients treated with catumaxomab, especially in the gastric cancer subset. The median puncture-free survival was 37 vs 14 days (P < .0001) for all patients, and 44 vs 15 days (P < .0001) for gastric cancer patients.

Median time to next puncture (puncture-free time) totaled 80 vs 15 days (P < .0001) for all patients and 118 vs 15 days (P < .0001) for gastric cancer patients, Dr. Parsons reported.

Futhermore, time to disease progression was significantly prolonged with treatment, reaching 110 days with catumaxomab vs 34 days in the whole group (P < .0001) and 110 vs 35 days in the gastric cancer subset (P < .0001).

Overall survival was also significantly improved in the gastric cancer group, 71 days vs 44 days (P = .03), but was similar for the overall group, 52 days vs 49 days (P = .42).

“We saw a significant survival advantage in the gastric cancer subgroup, but this was not the primary endpoint, as patients could cross over from the control to the treatment arm,” he said.

Phase II studies in gastric cancer and ovarian cancer will have overall survival as the primary endpoint, he added.

Well tolerated

Catumaxomab was well tolerated, and more than 80% of patients received all infusions. About half the patients experienced symptoms related to cytokine release, primarily fever.

“Compared to conventional chemotherapy, the side effects are minimal,” Dr. Parsons noted.

It is not yet clear how this approach treats the ascites. “It is quite amazing,” Dr. Ströhlein commented.

This effect was observed somewhat accidentally after investigators chose to examine paracentesis fluid for the drug’s effect on cell kill. “It prevented reaccumulation of fluid, which we were not expecting,” he said.

Extended follow-up of these patients and preliminary results from additional studies are expected to be presented at ASCO 2008.