A phase I and pharmacologic evaluation of the DNA intercalator CI-958 in patients with advanced solid tumors

Citation
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
Citations number
18
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
6
Issue
10
Year of publication
2000
Pages
3885 - 3894
Database
ISI
SICI code
1078-0432(200010)6:10<3885:APIAPE>2.0.ZU;2-9
Abstract
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.