Vorinostat (V) intratumoral levels and biomarker response in a window of opportunity trial in patients with resectable aerodigestive tract cancer.

Abstract

7022 Background: Aerodigestive tract cancer (ADT) is the leading cause of cancer-related death in the US. New effective treatments are needed. Among a panel of drugs causing growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor V was found most potent. To translate studies into the clinic, a window of opportunity trial of V was conducted. Methods: Pts with resectable ADT received 400 mg V once daily orally for 7 days prior to surgical resection. Serum samples were obtained before the last V dose and at the time of biopsy. Tumor tissue was immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. Post- versus pre-treatment tumor biopsies were scored for necrosis, acute and chronic inflammation, and immunohistochemical changes in Ki-67, cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent resection and had adequate pretreatment samples. Median age 66, 4 women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and tumor (7pts) concentrations above the detection limits. There was considerable interindividual variation in plasma V concentrations (7.3-192.4 ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation in the post-treatment biopsies. Most cases with KRAS mutations had biomarker responses. Changes in multiple biomarkers were observed across the range of intratumoral V levels. Conclusions: This is the first report of V concentrations in human tumors. Preoperative treatment with V achieved intratumoral concentrations comparable to serum with evidence of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses in resected ADT. The results demonstrate the value of window of opportunity trials in the investigation of novel cancer therapeutics.