Phase II trial of valproic acid combined with cisplatin-based chemoradiation in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) patients (pts).

Abstract

e17546 Background: Cisplatin-based chemoradiation (CRT) offers LA HNSCC pts a high local control rate, however, relapses are frequent. Here we evaluated if epigenetic regulation by VA, a histone deacetylase inhibitor (HDACi), combined with CRT in LA HNSCC improves response rate (RR). Methods: Patients with unresectable oropharynx (OP) and oral cavity LA HNSCC were included in this Simon two-stage phase II trial. After two weeks of VA (P1), CRT was initiated. Primary goal was RR at 8 weeks after CRT+VA (P2) by RECIST v 1.1. 8/20 and 25/32 responses were needed in the first and second stages for the trial to be considered positive (α = 0.05, β = 0.2). MicroRNA (miR) PCR-array profiling in plasma samples at baseline, P1 and P2, was compared to healthy controls by two sample t-test for each miR. Distribution of p-values was analyzed by beta-uniform mixture. HDAC2 and HR23B tumor immunohistochemistry were also evaluated. Results: Ten LA p16 negative OP pts were included. High-risk HPV was detected in 3 pts samples. Median age was 55 years (41-65). All pts were male, smokers or ex-smokers and with previous moderate/high alcohol intake. Due to significant toxicities seen in an interim safety analysis, accrual was terminated. A RR of 88% was achieved in 9 evaluable pts. A total of 169 miRs were differently expressed among pts and controls (FDR 0.05), including lower expression of known tumor suppressors (TS) such as miR-31, -222, -let-7b and -145. There were no significant differences in the pattern of miR expression at P1 vs. baseline. P2 vs. baseline had lower levels of miR-31, particularly in responders (p 0.007). TCGA HNSCC pts with low levels of miR-31 had a trend towards higher relapse free survival (HR 1.11, 95% CI 0.99-1.25; p = 0.073). Non-responders had no difference in miR expression between baseline and P2. HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease free survival. Conclusions: Although improved RR was seen with VA+CRT, prohibitive toxicities prevented the trial from continuing. Cancer pts and controls had distinct pattern of miR expression, mainly with low levels of TS targeting TP53. miR-31 deregulation in HNSCC needs to be further elucidated. Clinical trial information: NCT01695122.