6065 Background: Unresectable recurrent and metastatic SCCHN is incurable and associated with dismal prognosis. Our objective is to evaluate the clinical activity of depsipeptide (DEP) and its effects of on PBMCs, SCCHN tumors and oral mucosa tissues in an NCI/CTEP sponsored phase II trial. Methods: Eligibility criteria include PS 0–2, any number of prior therapies and no history of significant cardiovascular disease. DEP was administered at 13 mg/m2 IV over 4 hrs on days 1, 8, and 15 of 28 day cycles. A two-stage design was utilized, with commencement to the second stage (total 46 pts) if at least 8 of 18 pts achieve disease control at 8 weeks by RECIST. Results: To date, 10 pts (7M/3F) have been accrued, all with samples for correlative studies. Two pretreated pts (2 and 4 prior therapies for recurrent/metastatic disease) have achieved disease stabilization, including one with clear histone H3 hyperacetylation in PBMCs immediately following the first 4 hr infusion of DEP. Common toxicities to date have included fatigue and weakness, usually mild. Myelosuppression is uncommon. Aside from G3 hypotension in 1 pt, no cardiovascular toxicities have been attributed to DEP. To date, 2 of 2 pairs of pre- and post-treatment (cycle 1, day 16) biopsy specimens have demonstrated increased expression of p21Waf1/Cip1 by immunohistochemistry post-DEP, consistent with HDAC inhibition by DEP in tumor cells. Additionally, 3 pairs of tumor biopsies and 4 pairs of mucosal brush biopsies have been analyzed by differential gene expression profiling using microarrays containing 27,323 cDNA clones; 208 cDNA clones of interest appear to be upregulated in response to DEP in at least 3 of the 7 comparisons. Analysis also includes CpG island methylation status of candidate tumor suppressor loci in tumor and mucosal tissues. Conclusions: DEP appears well tolerated by SCCHN pts, with infrequent myelosuppression and minimal if any cardiovascular toxicity in pts without pre-existing disease. Effects of DEP on PBMCs, tumor and mucosal tissues are consistent with HDAC inhibition in vivo. Accrual to the clinical trial is ongoing. Supported by ASCO Career Development Award, NIH CA110342 and N01-CM-62204. No significant financial relationships to disclose.