Abstract OT1-4-05: Phase I dose-escalation study of oral administration of abexinostat (S 78454, PCI-24781) given with tamoxifen 20 mg in the treatment of patients with advanced breast cancer
Authors: Cortes J , Zucali PA , Santoro A , Munoz-Couselo E , Arnedos M , Cantero F , Kloos I , Depil S , Thomas E , Delaloge S 
Published: August 2014

Abstract
Background: Around 20% of patients initially diagnosed with local stage breast cancer will develop metastatic breast cancer, with an about 23% median 5-year survival rate from diagnosis. Patients whose tumors express ER and PR (ER+, PR+) are frequently treated with antiestrogens and aromatase inhibitors (AI). Primary and secondary resistances to hormone therapy lead to tumor progression and shorten survival expectancy.
In preclinical models, treatment of ER+ breast cancer cells with HDAC inhibitors leads to transcriptional down regulation and post-translation modification of the ER. This treatment reverses tamoxifen-induced ER stabilization, followed by induction of pro-apoptotic genes and apoptotic cell death. Epigenetic modulation of ER signaling by HDAC inhibitor represents a novel strategy to reverse hormonal resistance.
Abexinostat is a hydroxamate-based pan-HDAC inhibitor of class I/II, in phase I/II clinical trials. Abexinostat inhibits tumor growth in a panel of commonly used ER+ breast cancer cell lines including ATCC and NCI. Abexinostat potentiates the anti-tumor activity of tamoxifen in vitro in ER+ breast cancer cells, by down-regulation of ER protein expression and its pro-growth response genes (PgR, Cyclin D). It abrogates AKT cell signaling by directly down-regulating AKT1 at the transcriptional and post-translational level. Furthermore, cell death is induced by activating the apoptotic program.
Study design: phase I dose-finding of abexinostat for 4 consecutive days each week of a 3-week cycle given in combination with daily tamoxifen at 20 mg. Dose levels of abexinostat, 120, 140 and 160 mg bid, of 3 to 6 patients will be explored. Two dose de-escalation levels (100/80 mg) are allowed depending on toxicity. Dose-Limiting Toxicities assessment will be done at the end of cycle 2. Once the Maximum Tolerated Dose is determined up to 20 additional patients will be treated at the recommended dose in a confirmatory cohort.
Main eligibility criteria: Female≥ 18 years with histologically confirmed primary adenocarcinoma of the breast; ER+ (IHC≥ 10%), HER2- tumors. Patients must have had tumor progression on an AI administered for advanced/metastatic disease OR recurrence while on or within 12 months of completion of adjuvant AI, OR recurrence within 12 months of adjuvant tamoxifen completion and must have had up to 3 prior chemotherapy regimens in metastatic/advanced setting. Patients must have progressive tumor measurable or evaluable (RECIST criteria version 1.1).
Main objectives: Primary: to assess the safety and the tolerability of the combination treatment and to determine a recommended Phase II dose. Secondary: to determine the pharmacokinetic profile of both the drugs in combination and metabolites; to measure tumor response to the combination; to measure drug target inhibition by assessing acetylation state of histones proteins, HbF level and HDAC2 expression in peripheral blood mononuclear cells and in peripheral blood samples; to assess circulating tumor cells; to analyze biomarkers on tissue sample and pharmacogenomic of genes implicated in the metabolism of combination (optional).
Status: Study opened in September 2012, currently recruiting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-05.