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.

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, Comparative Study, 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
hdl.handle.net/1765/10327
Clinical Cancer Research
Erasmus MC: University Medical Center Rotterdam

van Zuylen, C, Mueller, C, Verweij, J, Ledermann, J.A, Bridgewater, J, Sparreboom, A, … Bootle, D. (2004). Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer. Clinical Cancer Research. Retrieved from http://hdl.handle.net/1765/10327