A phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies

Manuel Hidalgo, Gladys Rodriguez, John G. Kuhn, Thomas Brown, Geoffrey Weiss, J. Patrick MacGovren, Daniel D. Von Hoff, Eric K. Rowinsky

Research output: Contribution to journalArticle

Abstract

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 languageEnglish (US)
Pages (from-to)2763-2770
Number of pages8
JournalClinical Cancer Research
Volume4
Issue number11
StatePublished - Nov 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hidalgo, M., Rodriguez, G., Kuhn, J. G., Brown, T., Weiss, G., MacGovren, J. P., Von Hoff, D. D., & Rowinsky, E. K. (1998). A phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies. Clinical Cancer Research, 4(11), 2763-2770.