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Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies

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Abstract

This was a dose escalation Phase 1 trial designed todetermine the maximum tolerated dose (MTD) and dose-limitingtoxicities (DLT) of DENSPM. Methods: Adult patientswith refractory solid tumors were treated with DENSPMadministered by intravenous infusion in 100 ml of normalsaline over 30 minutes. The daily dose of DENSPM was dividedinto three equal doses administered approximately every eighthours for six days. Courses were repeated every 28 days.Results: Twenty-eight patients were enrolled in thestudy. Dose levels of DENSPM explored were 25mg/m2/day (3 patients), 50 mg/m2/day (9patients), 60 mg/m2/day (5 patients), 75mg/m2/day (6 patients), 94 mg/m2/day (3patients) and 118 mg/m2/day (2 patients). The DLTfor DENSPM was central nervous system toxicity characterizedby aphasia, ataxia, dizziness, vertigo and slurred speechoccurring at dose levels ≥ 94 mg/m2/day, whichwas also the MTD. Safety: The most frequent drug-relatedadverse events were asthenia (9 patients), injection sitereaction (6 patients) and anemia (6 patients). One patient wasremoved from the study due to CNS toxicity. There were notreatment-related deaths. No trends were observed regardinghematologic toxicities, biochemical changes or changes invital signs. Efficacy: Nineteen of the 28 patients enrolled inthe study were assessed for response. No objective responseswere observed. Five patients had stable disease as the bestresponse to therapy. Conclusions: Because the DLT wasCNS and because of the relatively low doses that could besafely administered on this schedule as compared with aonce-a-day schedule, this regimen was not recommended forPhase 2.

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Streiff, R.R., Bender, J.F. Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies. Invest New Drugs 19, 29–39 (2001). https://doi.org/10.1023/A:1006448516938

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