LBH589, a Novel Deacetylase Inhibitor (DACi), Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL). Skin Gene Expression Profiles in the First 24 Hours Related to Clinical Response Following Therapy.

Background: LBH589 is a novel DACi in Phase I trials. Pre-clinical studies have demonstrated that DACi alter gene expression and other DACi have induced disease regression in CTCL. Indeed, CTCL is an ideal disease to assess variation in tumor gene expression over time following drug administration. In this study we evaluated the safety and activity of LBH589 in CTCL and examined changes in tumor gene expression in the first 24 hours following oral LBH589.

Methods: Pts with advanced-stage CTCL, who had progressed following prior systemic therapy were entered into the oral DLT dose level 30 mg M,W,F cohort (n=1), the subsequent MTD dose level 20 mg M,W, F weekly (n=9). LBH589 was continued until disease progression or unacceptable toxicity. Intensive cardiac monitoring was performed. Six pts had 3 mm punch biopsies from CTCL-involved skin lesions at 0, 4, 8 and 24 h after administration, which were subjected to gene expression profiling using Affymetrix U133 plus 2.0 GeneChips with 47,000 probesets. Alteration in gene expression patterns was confirmed by QRT-PCR of selected genes. Individual gene expression analysis is underway, utilizing set enrichment analysis to elucidate the functional categories which correlate with degree of patient response.

Results: 10 pts are currently evaluable for response. 2 of the pts attained a complete response (CR), 4 attained a partial response (PR), 1 achieved stable disease (SD) with ongoing improvement, and 2 progressed on treatment (PD). (RR = 6/10; 60%). Microarray data on 5 pts demonstrated distinct gene expression response profiles between pts. Individual gene expression within patient tumors varied over the timepoints in the first 24 hours following treatment. To demonstrate effects of LBH589 as an epigenetic modulator, global changes in gene expression patterns in responding versus progressing patients have been delineated. In addition, functional categories of genes which correlate with degree of patient response have been identified.

Conclusions: LBH589 induces CR’s in CTCL pts. Preliminary microarray analysis of tumor samples have identified distinct gene expression profiles.