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 malignancies

摘要: Purpose: SAM486A is a novel inhibitor of the polyamine biosynthetic enzyme S -adenosylmethionine decarboxylase (SAMDC). This study was performed to characterize toxicity profile and pharmacological behavior determine maximum tolerated dose (MTD) administered by 1-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced cancer. Experimental Design: Twenty-three received 46 cycles at levels ranging from 3.6 202.8 mg/m 2 /day. plasma concentrations were measured during first cycle pharmacokinetic pharmacodynamic evaluations. Paired tumor biopsy specimens pre- posttreatment obtained 1 patient assess impact on intratumoral enzymes metabolites involved pathway. Results: The dose-limiting this schedule myelosuppression. Nonhematological toxicities, including nausea, vomiting, anorexia, fatigue, mild moderate severity. MTD 102.4 Pharmacokinetic analyses demonstrated rapid initial decrease drug end infusion, followed long terminal elimination phase mean (± SD) half-life 65.4 ± 55.6 h. Dose area under concentration-time curve correlated appearance grade 4 neutropenia correlation coefficients 0.70 0.69, respectively. Analysis paired taken before after treatment metastatic melanoma revealed decreased SAMDC activity, increased ornithine putrescine, depleted decarboxylated spermine, all which are consistent proposed mode action SAM486A. Conclusions: well administration established Neutropenia curve. Pharmacodynamic assessment tumoral tissues changes polyamines their inhibition.