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 cured of peritoneal carcinomatosis from colon cancer. We performed a phase I trial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanced metastatic colorectal cancer. Patients and methods: From April to July 1997, six patients were included in the trail; they had a median age of 52 years, 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 pr:or lines of chemotherapy. A fixed dose of Is MIU/m(2) IL-2,was administered by subcutaneous injection and ArgB was delivered via continuous intravenous 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 toxicities. 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 disturbances. The maximum tolerated dose for ArgB was 3 g kg(-1) day(-1), in combination with IL-2 at 12 MIU m(2) day(-1). No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variations. Conclusion: This schedule with a high dose of ArgB proved to be highly toxic 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) day(-1) IL-2, every 8 h.