Acivicin is a glutamine analogue antimetabolite that inhibits several glutamate-dependent synthetic enzymes. Previous studies of this agent administered on a 72-h continuous i.v. infusion schedule every 3 weeks demonstrated a high rate of severe, albeit reversible, central nervous system (CNS) toxicity at the 30 mg/m2/day dose level. Animal studies have shown that the CNS toxicity of acivicin can be prevented by a concomitant infusion of amino acids postulated to block drug uptake in the CNS by a saturable transport system that is common to endogenous amino acids. This study evaluated the feasibility of escalating acivicin doses in cancer patients by administering acivicin with a concomitant 96-h i.v. infusion of a mixture of 16 amino acids (Aminosyn, 10%). Twenty-three patients with advanced malignancies were treated with acivicin on a 72-h continuous infusion schedule at doses ranging from 25 to 60 mg/m2/day every 3 weeks. Reversible, dose-limiting CNS toxicity, characterized by lethargy, confusion, and decreased mental status, occurred in the two patients enrolled at the 60 mg/m2/day dose level, precluding further dose escalation. The maximum tolerated dose (MTD) and recommended dose for additional evaluation of acivicin on this schedule is 50 mg/m2/day. Other toxicities observed were dose-related neutropenia that was grade 4 in four patients (four courses), complicated with fever in three of those patients, and grade 3-4 thrombocytopenia in three patients (three courses). Pharmacokinetics studies performed in 15 patients revealed that the acivicin plasma C(ss) increased from 0.44 μg/ml (range, 0.28-0.59 μg/ml) at the 25 mg/m2 day to 1.06 μg/ml (0.64-1.5 μg/ml) at the 50 mg/m2/dose level. Acivicin C(ss) at the MTD was not significantly higher than previously reported values with single- agent acivicin on the same schedule of administration at the MTD of 25 mg/m2/day dose level (0.60 μg/ml; range, 0.43-0.81 μg/ml). Neurotoxicity did not correlate with acivicin C(ss), but relationships between exposure to acivicin and the occurrence of both neutropenia and thrombocytopenia were well described by a sigmoidal E(max) model. This trial demonstrated that concomitant infusions of amino acid can prevent acivicin-induced CNS toxicity, which allows the dose of acivicin to be escalated 2-fold above previously tolerable doses; however, this effect did not translate in a significant increment in acivicin C(ss).
|Original language||English (US)|
|Number of pages||8|
|Journal||Clinical Cancer Research|
|State||Published - Nov 1 1998|
ASJC Scopus subject areas
- Cancer Research