title: Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic colorectal cancer.
abstract: BACKGROUND
  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.
  
  
  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 1 with normal biological functions. All patients had received at least two prior lines of chemotherapy. A fixed dose of 18 MIU/m2 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 m2 day(-1). No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variations.
  
  
  CONCLUSIONS
  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 200000 UI kg(-1) day(-1) IL-2, every 8 h.
authors.affiliation: Centre René Gauducheau, CRLCC Nantes-Atlantique, Saint-Herblain, France. s-scientifique@nantes.fnclcc.fr
authors.forename: J Y
authors.initials: JY
authors.lastname: Douillard
authors.forename: J
authors.initials: J
authors.lastname: Bennouna
authors.forename: F
authors.initials: F
authors.lastname: Vavasseur
authors.forename: R
authors.initials: R
authors.lastname: Deporte-Fety
authors.forename: P
authors.initials: P
authors.lastname: Thomare
authors.forename: F
authors.initials: F
authors.lastname: Giacalone
authors.forename: K
authors.initials: K
authors.lastname: Meflah
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000368:Aged; D000818:Animals; D001120:Arginine / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051381:Rats; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D001120:Arginine