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

PURPOSE: The purpose of our study was to determine the maximum-tolerated\n dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the\n polyamine synthesis inhibitor SAM486A given in combination with\n 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL\n DESIGN: Patients with advanced colorectal cancer were treated with 5-FU\n [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV\n (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3\n days. Plasma sampling was performed to characterize the pharmacokinetics\n and pharmacodynamics of the combination RESULTS: Twenty-seven patients\n with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were\n treated. Twenty-six patients received SAM486A in the combination at doses\n ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of\n fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included\n neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and\n constipation. Fifteen of 26 patients evaluable for best response according\n to the Southwest Oncology Group criteria achieved a partial response [8\n (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence\n the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that\n when used as a single agent. CONCLUSIONS: The novel molecular agent\n SAM486A is tolerable and safe in combination with a standard 5-FU regimen\n in patients with advanced colorectal cancer. The dose of SAM486A\n recommended for additional studies with this combination is 125\n mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen\n is warranted