Phase I and Pharmacokinetic Study of the Polyamine Synthesis Inhibitor SAM486A in Combination with 5-Fluorouracil/Leucovorin in Metastatic Colorectal Cancer

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

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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/m2) followed by a 22-h infusion (600 mg/m2)] 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/m2/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m2/ 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/m2/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Original languageEnglish
Pages (from-to)1949-1955
Number of pages7
JournalClinical Cancer Research
Issue number6
Publication statusPublished - 15 Mar 2004
Externally publishedYes

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