Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine.


METHODS
Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi).


RESULTS
At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi.


CONCLUSIONS
The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.
Cancer Research Campaign Institute for Cancer Studies, The University of Birmingham Medical School, United Kingdom.
C V
CV
Christodoulou
D R
DR
Ferry
D W
DW
Fyfe
A
A
Young
J
J
Doran
T M
TM
Sheehan
A
A
Eliopoulos
K
K
Hale
J
J
Baumgart
G
G
Sass
D J
DJ
Kerr
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C020528:titanocene dichloride