Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Lia van Zuylen, John Bridgewater, Alex Sparreboom, Ferry A L M Eskens, Peter de Bruijn, Ivo Sklenar, Andre S T Planting, Les Choi, Douglas Bootle, Christian Mueller, Jonathan A Ledermann, Jaap Verweij
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 6 Pg. 1949-55 (Mar 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15041711 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Comparative Study, Journal Article)

Chemical References

• Amidines
• Antineoplastic Agents
• Indans
• 4-amidinoindan-1-one 2'-amidinohydrazone
• Leucovorin
• Fluorouracil

Topics

• Adult
• Aged
• Amidines (administration & dosage, pharmacokinetics, toxicity)
• Antineoplastic Agents (administration & dosage, pharmacokinetics, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use, toxicity)
• Colonic Neoplasms (drug therapy, pathology)
• Colorectal Neoplasms (drug therapy, parasitology)
• Female
• Fluorouracil (administration & dosage)
• Humans
• Indans (administration & dosage, pharmacokinetics, toxicity)
• Infusions, Intravenous
• Leucovorin (administration & dosage)
• Male
• Middle Aged
• Neoplasm Metastasis
• Pseudomyxoma Peritonei (drug therapy, pathology)
• Rectal Neoplasms (drug therapy, pathology)
• Treatment Outcome