Phase I study of CI-958 in children and adolescents with recurrent solid tumors

BACKGROUND. CI-958 is a synthetic intercalating agent of a new chemical class, the benzopyranoindazoles, with promising preclinical activity. Its mechanism 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 agent to pursue in Phase I clinical trials in children. METHODS. Children and adolescents with recurrent solid tumors received CI-958 at an initial dose of 450 mg/m² over 2 hours. Dose escalation was performed in a standard fashion in cohorts of three patients until dose limiting toxicity and the maximum tolerated dose were determined. RESULTS. Twenty-one patients were entered on the study. The maximum tolerated dose was found to be 650 mg/m². Dose limiting toxicities were Grade 4 neutropenia and Grade 4 hypotension at the dose level of 700 mg/m². CONCLUSIONS. The maximum tolerated dose of CI-958 in children and adolescents is 650 mg/m². No antitumor activity has been observed.