title: Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer.
abstract: OBJECTIVE
  The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.
  
  
  METHODS
  Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination
  
  
  RESULTS
  Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent.
  
  
  CONCLUSIONS
  The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.
authors.affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands. c.vanzuylen@erasmusmc.nl
authors.forename: Lia
authors.initials: L
authors.lastname: van Zuylen
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.forename: Ivo
authors.initials: I
authors.lastname: Sklenar
authors.forename: Andre S T
authors.initials: AS
authors.lastname: Planting
authors.forename: Les
authors.initials: L
authors.lastname: Choi
authors.forename: Douglas
authors.initials: D
authors.lastname: Bootle
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000578:Amidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000469:parasitology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011553:Pseudomyxoma Peritonei / Q000188:drug therapy / Q000473:pathology; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D007189:Indans; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D002955:Leucovorin; D005472:Fluorouracil