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 Css increased from 0.44 microg/ml (range, 0.28-0.59 microg/ml) at the 25 mg/m2/day to 1.06 microg/ml (0.64-1.5 microg/ml) at the 50 mg/m2/dose level.
Acivicin Css 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 microg/ml; range, 0.43-0.81 microg/ml). Neurotoxicity did not correlate with
acivicin Css, but relationships between exposure to
acivicin and the occurrence of both
neutropenia and
thrombocytopenia were well described by a sigmoidal Emax 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 Css.