Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies.
OBJECTIVE
This dose-escalating study investigated the toxicity, pharmacokinetics, and efficacy of the novel direct-acting antifolate ZD9331, given as a 5-day i.v. infusion every 3 weeks.


METHODS
Forty-five patients with refractory solid malignancies received ZD9331, which was escalated from 0.125 mg/m(2)/day.


RESULTS
Dose-limiting grade 4 thrombocytopenia occurred in 3 of 6 patients treated at 8 mg/m(2)/day; other drug-related toxicities, across dose levels, included skin and gastrointestinal toxicity, lethargy, and asymptomatic, reversible, elevated transaminases. The maximum plasma concentration and area under the curve increased with dose. Clearance was dose-dependent and predominantly renal. At doses >/=2.4 mg/m(2)/day, plasma 2'-deoxyuridine levels were elevated consistently indicating inhibition of thymidylate synthase. Two patients had a partial response (breast, 1 patient; ovarian, 1 patient), and 10 patients had stable disease.


CONCLUSIONS
The maximum tolerated dose was defined as 6 mg/m(2)/day, and the toxicity profile for this regimen was considered acceptable and manageable. Administration of ZD9331 lead to elevation of 2'-deoxyuridine levels, signifying thymidylate synthase inhibition, and evidence of antitumor activity was observed.
Rees
Charlotte
C
Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Beale
P
P
Trigo
Jose Manuel
JM
Mitchell
Fraser
F
Jackman
Anne
A
Smith
Robert
R
Douglass
Edwin
E
Judson
Ian
I
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D011799:Quinazolines; C094299:ZD 9331