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• W4247245767 abstract "Abstract Background: Despite the anticancer activity of Pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors to target individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of Ricolinostat (the leading HDAC6 inhibitor) in breast cancer patients. Methods: We have developed a computational algorithm based on mRNA expression profiling that evaluates the activity of the HDAC6 regulon (HDAC6-score). Through preclinical in vitro and in vivo studies, we confirmed that high HDAC6-score correlates with the anticancer response of breast cancer (BC) cells to Ricolinostat treatment and consequently can be used as a predictive biomarker. Thus, we studied ~3,000 primary human cancers and found that a group of ~20% of breast cancers presents high HDAC6-scores. Based on these results, we designed a phase I-II clinical trial (n=16 patients, pts) to determine the maximum tolerated dose (MTD) of Ricolinostat when given daily on days 1-21 of the 28-day treatment cycle in combinations with a fixed dose of Abraxane of 100 mg/m2 administered on days 1, 8, and 15 of the 28-day treatment cycle. Additionally, our study also includes secondary endpoints correlating patient response with the HDAC6-score. Results: Our results, showed that: 1) No dose-limiting toxicities (DLT) were seen and the maximum tolerated dose (MTD) was not reached). 2) In patients with measureable disease (n=15), the following were best responses: 2 partial response (PR), 11 stable diseases (SD), and 2 progressive diseases (PD: 1 TNBC, 1 HR+/HER2-) (Waterfall Plot). Three patients who previously received a taxane in the metastatic disease achieved stable disease with Ricolinostat plus nab-paclitaxel. One patient with SD remains on treatment since Feb 2018 (17 months). The clinical benefit rate was 31.25%: 5/16 patients (2 PR + 3 SD &gt; 6 months). All of these patients were diagnosed with HR+/HER2- metastatic breast cancer, except 1 stable disease with TNBC. Median PFS was 5.3 months [95% confidence interval (CI): 4.45-11.0]. 3) Patients with high HDAC6 score had a significantly improved PFS compared to low HDAC6 score (6.6 months vs. 2.0 months, respectively p=0.01). Conclusions: Ricolinostat 240 mg qd is safe and tolerable with weekly nab-paclitaxel. Clinical activity has been observed, with the majority of patients demonstrating SD and 1 with a PR. High HDAC6-score associates with longer PFS and should be evaluated in larger trials as a predictor of response to HDAC6 inhibition. Finally, we also expanded our studies to other tumor types and validated multiple tumor type-specific HDAC6-scores. These results open the exciting possibility of coupling Ricolinostat treatment with HDAC6-score as a predictive biomarker for treating human cancers. Citation Format: Jose Silva, Kevin Kalinsky, Cody Chiuzan, Tizita Zeleke, Pan Qingfei, Jiyang Yu. Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT107." @default.
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• W4247245767 date "2020-08-15" @default.
• W4247245767 modified "2023-10-16" @default.
• W4247245767 title "Abstract CT107: Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC)" @default.
• W4247245767 doi "https://doi.org/10.1158/1538-7445.am2020-ct107" @default.
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