Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (CGP 48 664) in patients with solid tumors

A single-agent dose-escalating Phase I and pharmacological study of the pol yamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patien ts were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 1 6, 32, 48, 70, 110, 170, 270, and 325 mg/m(2)/week. Pharmacokinetic samplin g was done on day 1, and trough samples were taken weekly during the first treatment cycle. Pharmacodynamic sampling was done on days 1 and 22, At 325 mg/m(2)/week, dose-limiting toxicity was seen (one patient each with grade 4 febrile neutropenia, grade 3 neurotoxicity, and grade 3 hypotension with syncope and T-wave inversions on electrocardiogram). The recommended dose for further testing was set at 270 mg/m(2)/week, Infusion time was increase d from 10 to 180 min due to facial paresthesias and flushing and somnolence . Drug exposure increased linearly with dose. Mean +/- SD t(1/2) at 70-325 mg/m(2) doses was 61.4 +/- 26.2 h, with a large volume of distribution at s teady state. In peripheral blood leukocytes, a clear relationship between d ose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 386A can be administ ered safely using a dosing regimen of four weekly infusions followed by 2 w eeks off therapy. The recommended dose for Phase II studies using this regi men is 270 mg/m(2)/week.