CI-980 for the treatment of recurrent or progressive malignant gliomas: National Central Nervous System Consortium phase I-II evaluation of CI-980

Objective: The purpose of this phase I/II trial was to determine the maximal tolerated dose of CI-980, and determine efficacy against malignant glioma. Background: The CI-980 is a synthetic mitosis inhibitor that acts via the colchicine binding site on tubulin. Broad in vitro activity has been seen in a variety of human and murine tumor models. Phase I studies have demonstrated schedule dependent toxicity of CI-980. Dose-limiting toxicity was neurologic when CI-980 was given as a 24-hr infusion and hematologic when given over 72 hr at higher doses. Methods: Twenty-four patients ages 29-65 entered this study. Six patients were treated on the phase I arm at three escalating dose levels ranging from 10.5 to 13.5 mg/m², given over 72 hr. Eighteen patients were then treated at the highest tolerated dose, 13.5 mg/m² per cycle. Treatment response was based on serial MRI imaging characteristics. Results: The phase II study was stopped at the end of the first stage due to poor treatment response. There were no partial or complete responses, (0/24) 95% CI = 0-14%. Four patients (4/24) had a best treatment response of stable disease/no change. Median time to progression for all patients was 6.4 weeks (95% CI: 6-9 weeks). Dose-limiting toxicity was grade 3-4 granulocytopenia. Three episodes of neurotoxicity manifested by a moderate cerebellar dysfunction were seen. Conclusions: These results fail to demonstrate the significant activity of CI-980 against recurrent glioma.