Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic colorectal cancer

Introduction: Interleukin-2 (IL-2) and sodium butyrate allow rats to be cur ed of peritoneal carcinomatosis from colon cancer. We performed a phase I t rial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanc ed metastatic colorectal cancer. Patients and methods: From April to July 1 997, six patients were included in the trail; they had a median age of 52 y ears, four had a performance status of 0, two had a performance status of I with normal biological functions. All patients had received at least two p r:or lines of chemotherapy. A fixed dose of Is MIU/m(2) IL-2,was administer ed by subcutaneous injection and ArgB was delivered via continuous intraven ous infusion on days 1-6 with escalating doses starting at 2 g kg(-1) day(- 1). Results: The planned dose escalation was not possible because of toxici ties. A daily ArgB dose of 2 g/kg was delivered for nine cycles. Level 2 (4 g/kg) could not be delivered in three of the six patients because of liver toxicity. The dose-limiting toxicities were fatigue and liver function dis turbances. The maximum tolerated dose for ArgB was 3 g kg(-1) day(-1), in c ombination with IL-2 at 12 MIU m(2) day(-1). No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variation s. Conclusion: This schedule with a high dose of ArgB proved to be highly t oxic with liver insufficiency. We will be running another trial with lower doses of ArgB calculated from the schedule used in the experimental model, starting at a dose of 20 mg kg(-1) day(-1) for ArgB and 200 000 UI kg(-1) d ay(-1) IL-2, every 8 h.