Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia

• Published in: Clinical cancer research 1998-02, Vol.4 (2), p.303-310
• Main Authors: M F Mitchell, G Tortolero-Luna, J J Lee, W N Hittelman, R Lotan, J T Wharton, W K Hong, K Nishioka
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Arginine - blood; Biogenic Polyamines - metabolism; Biological and medical sciences; Cervical Intraepithelial Neoplasia - drug therapy; Cervical Intraepithelial Neoplasia - pathology; Chemotherapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Eflornithine - adverse effects; Eflornithine - therapeutic use; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Female; Humans; Medical sciences; Ornithine - blood; Ornithine Decarboxylase - metabolism; Pharmacology. Drug treatments; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - pathology
• ISSN: 1078-0432; 1557-3265

alpha-Difluoromethylornithine (DFMO) is a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a dose de-escalation Phase I trial of DFMO in patients with grade 3 cervical intraepithelial neoplasia to determine an optimal dose of DFMO using ornithine decarboxylase activity and polyamine modulation as surrogate biomarkers and to evaluate its toxicity. Thirty patients with biopsy-confirmed grade 3 cervical intraepithelial neoplasia were assigned sequentially to one of five DFMO doses (1.000, 0.500, 0.250, 0.125, or 0.060 g/m2) given daily for 31 days. One patient was excluded from analysis for protocol violation. Polyamine levels were assessed in cervical tissue, plasma, and RBCs. Tissue and blood samples were obtained before and after treatment with DFMO. All patients underwent loop excision of the cervix at the end of the study for complete histological evaluation and definitive treatment of the premalignant condition. No major clinical toxicity was observed at any DFMO dose. A reduction in tissue spermidine to spermine (SPD:SPM) ratio and an increase in plasma arginine levels were observed among patients receiving 1.000 g/m2/day (P < 0.05). A nonsignificant reduction in SPD:SPM ratio was also observed in the 0.500 g/m2/day dose group, and a nonsignificant increase in plasma arginine level was observed down to the 0.125 g/m2/day dose level. There was no evidence of modulation of other polyamines or precursors. Fifteen patients experienced a complete (5 patients) or partial (10 patients) histological response. In conclusion, DFMO was well tolerated and significantly modulated tissue SPD:SPM ratio and plasma arginine level at the dose of 1.000 g/m2/day. To clarify whether DFMO has activity at lower doses, these results will be tested in a three-armed double-blinded Phase II study using placebo and DFMO doses of 0.500 and 0.125 g/m2/day.