Abstract 412P
Background
The prognosis of patients diagnosed with peritoneal metastasized (PM) colorectal cancer who are ineligible for cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is poor. We hypothesize that adding intraperitoneal (IP) irinotecan to standard systemic palliative chemotherapy improves the prognosis of these patients. Therefore we conducted this phase I trial.
Methods
We performed a classic 3+3 open label phase I trial (Netherlands Trial Register number NL6988) in patients diagnosed with PM colorectal cancer for whom a CRS-HIPEC procedure was no option. IP irinotecan in combination with i.v. FOLFOX-bevacizumab was administered every 2 weeks. Determination of the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) were primary objectives, while investigating the systemic and IP pharmacokinetics, safety profile, feasibility and effectiveness of IP irinotecan were secondary objectives.
Results
A total of 18 patients were treated in this study. No DLTs were observed in patients treated with 50 mg (n=4) or 75 mg (n=9) of IP irinotecan. Two DLTs (i.e. diarrhea grade 3, and a 2-week dose delay due to neutropenia and paralytic ileus, respectively) were observed within the 100 mg irinotecan dose-level (n=5). The MTD was set at 75 mg IP irinotecan, which was well tolerated with a median of 12 administered cycles per patient. Compared to the systemic exposure of the active irinotecan-metabolite SN-38, the IP SN-38 exposure was high with a median AUCip/AUCiv ratio of 4.6. A partial response was observed in 13 patients, while stable disease was seen in another 5 patients. Seven patients underwent a post-treatment diagnostic laparoscopy in which a complete peritoneal tumor response was observed in 4 patients; in 2 other patients, the majority of the tumor cells were avital.
Conclusions
In conclusion, 75 mg of IP irinotecan concomitant to FOLFOX-bevacizumab can safely be administered and is well tolerated. The IP formation of SN-38 results in a prolonged high IP exposure while the systemic exposure to SN-38 is low. Highly promising antitumor activity was seen, and therefore a phase II study has recently started.
Clinical trial identification
Netherlands Trial Register number NL6988.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Stichting Coolsingel.
Disclosure
R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Other, Patent pending: Pamgene; Financial Interests, Institutional, Research Grant: Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. All other authors have declared no conflicts of interest.