BACKGROUND. CI-958 is a synthetic intercalating agent of a new chemical cla
ss, the benzopyranaindazoles, with promising preclinical activity. Its mech
anism of action is thought to be stabilization of the cleavable complex of
DNA with topoisomerase II, as well as DNA helicase blockade. It is thought
to have less cardiotoxicity than the anthracyclines. Early Phase I studies
in adults showed the drug to be well tolerated, making it an attractive age
nt to pursue in Phase I clinical trials in children.
METHODS. Children and adolescents with recurrent solid tumors received CI-9
58 at an initial dose of 450 mg/m(2) over 2 hours. Dose escalation was perf
ormed in a standard fashion in cohorts of three patients until dose limitin
g toxicity and the maximum tolerated dose were determined.
RESULTS. Twenty-one patients were entered on the study. The maximum tolerat
ed dose was found to be 650 mg/m(2). Dose limiting toxicities were Grade 4
neutropenia and Grade 4 hypotension at the dose level of 700 mg/m(2).
CONCLUSIONS. The maximum tolerated dose of CI-958 in children and adolescen
ts is 650 mg/m(2). No antitumor activity has been observed. Cancer 2001;91:
1166-9. (C) 2001 American Cancer Society.