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A Phase I and Pharmacokinetic Study of SAM486A, a Novel Polyamine Biosynthesis Inhibitor, Administered on a Daily-times-five every-three-week Schedule in Patients with Advanced Solid Malignancies¹

Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78229 [L. L. S., E. K. R., L. A. H., G. R. W., M. H., G. M. C., J. M., D. D. V. H., S. G. E.]; Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [G. G., C. W. P.]; Novartis Pharmaceuticals Corp., East Hanover, New Jersey 07936; and Novartis Pharma AG, Basel, Switzerland CH-4002 [L. C., R. L., N. C. B., I. T. S., R. C.]

Purpose: SAM486A is a novel inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC). This study was performed to characterize the toxicity profile and the pharmacological behavior and to determine the maximum tolerated dose (MTD) of SAM486A administered by a 1-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced cancer.

Experimental Design: Twenty-three patients received 46 cycles of SAM486A at dose levels ranging from 3.6 to 202.8 mg/m²/day. SAM486A plasma concentrations were measured during the first cycle for pharmacokinetic and pharmacodynamic evaluations. Paired tumor biopsy specimens pre- and posttreatment were obtained in 1 patient to assess the impact of SAM486A on intratumoral enzymes and metabolites involved in the polyamine biosynthetic pathway.

Results: The dose-limiting toxicity of SAM486A on this schedule was myelosuppression. Nonhematological toxicities, including nausea, vomiting, anorexia, and fatigue, were mild to moderate in severity. The MTD of SAM486A was 102.4 mg/m²/day. Pharmacokinetic analyses demonstrated a rapid initial decrease in plasma drug concentrations at the end of infusion, followed by a long terminal elimination phase with a mean (± SD) terminal elimination half-life of 65.4 ± 55.6 h. Dose and area under the concentration-time curve correlated with the appearance of grade 4 neutropenia with correlation coefficients of 0.70 and 0.69, respectively. Analysis of paired tumor biopsy specimens taken before and after SAM486A treatment in 1 patient with metastatic melanoma revealed decreased SAMDC activity, increased ornithine decarboxylase activity, increased levels of putrescine, and depleted levels of decarboxylated S-adenosylmethionine and spermine, all of which are consistent with the proposed mode of action of SAM486A.

Conclusions: SAM486A was well tolerated on this schedule of administration with the MTD established at 102.4 mg/m²/day. Neutropenia was dose-limiting and correlated with dose and area under the concentration-time curve. Pharmacodynamic assessment of tumoral tissues in 1 study patient demonstrated changes in the levels of polyamines and their biosynthetic enzymes consistent with SAMDC inhibition.

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