title: Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia.
abstract: 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.
authors.affiliation: Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Mitchell
authors.forename: G
authors.initials: G
authors.lastname: Tortolero-Luna
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.forename: W N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: R
authors.initials: R
authors.lastname: Lotan
authors.forename: J T
authors.initials: JT
authors.lastname: Wharton
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
authors.forename: K
authors.initials: K
authors.lastname: Nishioka
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001120:Arginine / Q000097:blood; D015317:Biogenic Polyamines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000518:Eflornithine / Q000009:adverse effects / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009952:Ornithine / Q000097:blood; D009955:Ornithine Decarboxylase / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D004791:Enzyme Inhibitors; D001120:Arginine; D009952:Ornithine; D009955:Ornithine Decarboxylase; D000518:Eflornithine