A phase I trial of panobinostat (<scp>LBH</scp>589) in patients with metastatic melanoma

<jats:title>Abstract</jats:title><jats:p>Epigenetic alterations by histone/protein deacetylases (<jats:styled-content style="fixed-case">HDAC</jats:styled-content>s) are one of the many mechanisms that cancer cells use to alter gene expression and promote growth. <jats:styled-content style="fixed-case">HDAC</jats:styled-content> inhibitors have proven to be effective in the treatment of specific malignancies, particularly in combination with other anticancer agents. We conducted a phase I trial of panobinostat in patients with unresectable stage <jats:styled-content style="fixed-case">III</jats:styled-content> or <jats:styled-content style="fixed-case">IV</jats:styled-content> melanoma. Patients were treated with oral panobinostat at a dose of 30 mg daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose interruption. Due to this, a second treatment arm was opened and the dose was changed to 30 mg oral panobinostat three times a week every other week (Arm B). Six patients were treated on Arm A and 10 patients were enrolled to Arm B with nine patients treated. In nine patients treated on Arm B, the response rate was 0% (90% confidence interval [CI]: 0–28%) and the disease‐control rate was 22% (90% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 4–55%). Among all 15 patients treated, the overall response rate was 0% (90% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0–17%) and the disease‐control rate was 27% (90% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 10–51%). There was a high rate of toxicity associated with treatment. Correlative studies suggest the presence of immune modifications after <jats:styled-content style="fixed-case">HDAC</jats:styled-content> inhibition. Panobinostat is not active as a single agent in the treatment of melanoma. Further exploration of this agent in combination with other therapies may be warranted.</jats:p>