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 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.