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Phase I and Pharmacological Study of Weekly Administration of the Polyamine Synthesis Inhibitor SAM 486A (CGP 48 664) in Patients with Solid Tumors

Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, 3000 CA Rotterdam, the Netherlands [F. A. L. M. E., C. v. Z., L. J. D., A. S. Th. P., J. V.]; City Hospital, D-90419 Nuerenberg, Germany [G. A. G., I. W., U. B.]; University Hospital, 9713 EZ Groningen, the Netherlands [F. A. M.]; New Drug Development Office, 1007 MB Amsterdam, the Netherlands [J. W.]; Novartis Pharma AG, Basel CH 4002, Switzerland [N. C. B., R. C.]; Novartis Pharma, East Hanover, New Jersey 07936 [L. C.]; and private practice, D-82515 Wolfrathausen Munich, Germany [A-R. H.]

A single-agent dose-escalating Phase I and pharmacological study of the polyamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patients were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 16, 32, 48, 70, 110, 170, 270, and 325 mg/m²/week. Pharmacokinetic sampling 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/m²/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/m²/week. Infusion time was increased 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/m² doses was 61.4 ± 26.2 h, with a large volume of distribution at steady state. In peripheral blood leukocytes, a clear relationship between dose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 486A can be administered safely using a dosing regimen of four weekly infusions followed by 2 weeks off therapy. The recommended dose for Phase II studies using this regimen is 270 mg/m²/week.

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