A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma

Abstract

PurposeVorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.ResultsThirty patients were enrolled. Median age of patients was 53 years (range 21–73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC. Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

“…HDAC inhibitors (HDACi) have been used in clinical phase 1 to 3 trials on patients with advanced solid tumors, leukemias, and lymphomas . A recent phase 2 trial of the HDAC inhibitor, vorinostat, in ACC has completed enrollment, but results have not be published; however, preliminary data was promising with three responses (2 partial and 1 minor), as well as improvement in symptoms in three additional patients out of the 30 patients enrolled …”

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

“…Unfortunately, there is no effective systemic treatment for advanced ACC as standard cytotoxic chemotherapy agents produce tumor response rates in the range of 5–15% without a clear impact on patient survival (5–7). Targeted agents including cetuximab, erlotinib, gefitinib, vorinostat, and others have also shown limited activity against ACCs (3;4;8;9). One potential target, the tyrosine kinase receptor KIT, is overexpressed in the majority of these tumors but treatment of ACC patients with the KIT inhibitor, imatinib, produced no or little clinical benefit (10–12).…”

Clinical trial of nintedanib in patients with recurrent or metastatic salivary gland cancer of the head and neck: A multicenter phase 2 study (Korean Cancer Study Group HN14‐01)

“…In contrast, a phase 2 study of sunitinib achieved prolonged tumor stabilization of more than 6 months in 62% of patients with documented prior progression . In another study examining vorinostat, which is a small‐molecule inhibitor of histone deacetylase, 1 of 30 patients exhibited a partial response, and 25 of 30 patients had SD as their best response . Recently, sorafenib and dovitinib, which target multiple receptor tyrosine kinases, also showed a median progression‐free survival longer than 6 months .…”