A Phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies.
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.
Hidalgo
M
M
Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio 78229, USA.
Rodriguez
G
G
Kuhn
J G
JG
Brown
T
T
Weiss
G
G
MacGovren
J P
JP
Von Hoff
D D
DD
Rowinsky
E K
EK
D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects; D004573:Electrolytes; D005260:Female; D005947:Glucose; D005973:Glutamine / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D057947:Parenteral Nutrition Solutions; D012996:Solutions; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D004573:Electrolytes; D007555:Isoxazoles; D057947:Parenteral Nutrition Solutions; D012996:Solutions; C545824:amino-acid, glucose, and electrolyte solution; D005973:Glutamine; D005947:Glucose; C006303:acivicin