Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(−1) on days 1–3, followed by doxorubicin (20 mg m(−2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(−1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(−1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for ⩾8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(−1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.