) This proposal describes a randomized, double blind, placebo controlled phase II clinical trial of N-(4-hydroxyphenyl) retinamide (4-HPR) versus 13-cis retinoic acid (13-cis RA) in oral dysplastic leukoplakia.
Its specific aims are to 1) establish surrogate endpoint biomarkers (SEBs) of oral mucosal carcinogenesis that are modulated by 4-HPR or 13-cis RA; 2) determine if oral 4-HPR or 13-cis RA will cause significant modulation of SEBs and significant regression or oral dysplastic leukoplakia; 3) determine differences between 4- HPR and 13-cis RA in their ability to modulate SEBs; and 4) document the degree of recurrence of oral dysplastic leukoplakia after termination of treatment. Thirty-two subjects will be accrued to each of three treatment arms (4-HPR, 13-cis RA, placebo) for a 12 month course randomized after 3 months to receive a full course of 4-HPR or 13-cis RA. Biopsies of leukoplakia and uninvolved mucosa will be taken repeatedly during the course of the study. As potential SEBs, PCNA, MIB-1, TGFa, C-erbB-2 (HER-2/neu) and EGFR expression will be analyzed by immunohistochemistry. To determine the cell or origin and to describe gene modulation at the transcriptional level, TGFa, C- erbB-2 (HER-2/neu) and EGFR expression will be studied using in-situ hybridization (ISH) and reverse transcriptase PCR (RT/PCR). This phase II trial is based on the results of a pilot study and will provide for intermediate endpoints that may predict later reduction in cancer incidence rates.
| Beenken, Samuel W; Hockett Jr, Richard; Grizzle, William et al. (2002) Transforming growth factor-alpha: a surrogate endpoint biomarker? J Am Coll Surg 195:149-58 |
