Phase I clinical and pharmacokinetic study of oral carboxyamidotriazole, a signal transduction inhibitor.
OBJECTIVE
We conducted a phase I trial of carboxyamidotriazole (CAI, NSC 609974), designed to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetic characteristics of CAI gelatin capsule (gelcap) formulation administered daily as a single oral dose.


METHODS
Twenty-nine patients with advanced malignancy who met standard eligibility criteria were treated with once-daily CAI given in cycles of 28 days. Pharmacokinetic sampling was performed on days 1 and 29 and trough plasma CAI levels were assessed weekly.


RESULTS
Patients were entered at dose levels of 50, 75, and 100 mg/m2. All three patients at the 100-mg/m2 level experienced dose-limiting neurocerebellar toxicity. Other neurotoxicities were mild. Gastrointestinal side effects were common, but generally mild, with 23 patients experiencing nausea and/or vomiting of any grade. Fatigue was a frequent complaint, with 19 patients experiencing mild to moderate symptoms. Six patients with nausea and vomiting and five with fatigue experienced relief of symptoms with a change to nocturnal administration of CAI. Peak plasma concentrations (Cp) occurred at 2.4 +/- 1.5 hours after administration of the oral gelcap dose. Patients approached steady-state trough plasma concentrations (Css) by days 8 to 15 and maintained a relatively constant Css throughout the course of treatment. For all patients, the mean variation in weekly CAI Cp was 12.4% +/- 5.3%.


CONCLUSIONS
The MTD for the gelcap formulation was 75 mg/m2 with dose-limiting neurocerebellar toxicity (ataxia) seen at 100 mg/m2. Other prominent side effects, including nausea, vomiting, and fatigue, were partially alleviated through altering the administration schedule to nighttime dosing.
Berlin
J
J
University of Wisconsin Comprehensive Cancer Center, Madison, USA. jdberlin@facstaff.wisc.edu
Tutsch
K D
KD
Hutson
P
P
Cleary
J
J
Rago
R P
RP
Arzoomanian
R Z
RZ
Alberti
D
D
Feierabend
C
C
Wilding
G
G
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002214:Capsules; D004064:Digestive System / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D005782:Gels; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D009420:Nervous System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D002214:Capsules; D005782:Gels; D014230:Triazoles; C062058:carboxyamido-triazole