Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule.
OBJECTIVE
To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m(2) with escalation based on a modified Fibonacci scheme.


METHODS
A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m(2) to 105 mg/m(2). Blood and urine samples were collected and 3-AP was measured by HPLC.


RESULTS
A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade l occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease.


CONCLUSIONS
Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m(2) on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.
Sylvester Cancer Center, 1475 N.W. 12th Avenue, Miami, Florida 33136, USA. lfeun@mednet.med.miami.edu
Lynn
L
Feun
Manuel
M
Modiano
King
K
Lee
John
J
Mao
Angela
A
Marini
Niramol
N
Savaraj
Patricia
P
Plezia
Bijan
B
Almassian
Elizabeth
E
Colacino
Jessica
J
Fischer
Susan
S
MacDonald
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D001778:Blood Coagulation Disorders / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced
D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone