Ec. Dees et al., A phase I and pharmacologic evaluation of the DNA intercalator CI-958 in patients with advanced solid tumors, CLIN CANC R, 6(10), 2000, pp. 3885-3894
5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]b benzothiopyrano[4
,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member o
f a new class of DNA intercalating compounds, the benzothiopyranoindazoles.
Because of its broad spectrum and high degree of activity as well as a fav
orable toxicity profile in preclinical models, CI-958 was chosen for furthe
r development. The Phase I study described here was undertaken to determine
the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-9
58 given as an i.v. infusion every 21 days, Adult patients with advanced re
fractory solid tumors who had adequate renal, hepatic, and hematological fu
nction, life expectancy, and performance status were eligible for this stud
y. Written informed consent was obtained from all patients, Patients receiv
ed a 1- or 2-h infusion of CI-958 at 21-day intervals. The starting dose wa
s 5.2 mg/m(2), and at least three patients were evaluated at each dose leve
l before proceeding to a new dose level, A pharmacokinetically guided dose
escalation design was used until reaching a predetermined target area under
the plasma concentration versus time curve (AUC), after which a modified F
ibonacci scheme was used. Forty-four patients (21 men and 23 women; median
age, 59 years) received 162 courses of CI-958, Neutropenia and hepatorenal
toxicity were the dose-limiting toxicities, which defined the maximum toler
ated dose of CI-958 to be 875 mg/m(2) when given as a 2-h infusion every 21
days. There were no tumor responses. Two patients had stable disease for >
250 days, The recommended Phase II dose is 560 mg/m(2) for patients with si
gnificant prior chemotherapy and 700 mg/m(2) for patients with minimal prio
r chemotherapy, Pharmacokinetic analysis of plasma and urine concentration-
time data from each patient was performed. At the recommended Phase II dose
of 700 mg/m(2), mean CI-958 clearance was 370 ml/min/m(2), mean AUC was 33
800 ng(.)h/ml, and mean terminal half-life (t(1/2)) was 15.5 days. The clea
rance was similar at all doses, and plasma CI-958 AUC increased proportiona
lly with dose, consistent with linear pharmacokinetics. The percentage redu
ction in absolute neutrophil count from baseline was well predicted by AUC
using a simple Emax model. The pharmacokinetically guided dose escalation s
aved five to six dose levels in reaching the maximum tolerated dose compare
d with a standard dose escalation scheme. This may represent the most succe
ssful application to date of this dose escalation technique.