This was a dose escalation Phase 1 trial designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of DENSPM.
Methods: Adult patients with refractory solid tumors were treated with DENSPM administered by intravenous infusion in 100 ml of normal saline over 30 minutes. The daily dose of DENSPM was divided into three equal doses administered approximately every eight hours for six days. Courses were repeated every 28 days.
Results: Twenty-eight patients were enrolled in the study. Dose levels of DENSPM explored were 25 mg/m2/day (3 patients), 50 mg/m2/day (9 patients), 60 mg/m2/day (5 patients), 75 mg/m2/day (6 patients), 94 mg/m2/day (3 patients) and 118 mg/m2/day (2 patients). The DLT for DENSPM was central nervous system toxicity characterized by aphasia, ataxia, dizziness, vertigo and slurred speech occurring at dose levels > or = 94 mg/m2/day, which was also the MTD.
Safety: The most frequent drug-related adverse events were asthenia (9 patients), injection site reaction (6 patients) and anemia (6 patients). One patient was removed from the study due to CNS toxicity. There were no treatment-related deaths. No trends were observed regarding hematologic toxicities, biochemical changes or changes in vital signs.
Efficacy: Nineteen of the 28 patients enrolled in the study were assessed for response. No objective responses were observed. Five patients had stable disease as the best response to therapy.
Conclusions: Because the DLT was CNS and because of the relatively low doses that could be safely administered on this schedule as compared with a once-a-day schedule, this regimen was not recommended for Phase 2.