Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC)

Background:HDAC6, a cytoplasmic histone deacetylase, impacts cell viability by influencing protein metabolism, microtubule dynamics, and chaperone function. ACY-1215 is an orally active, selective HDAC6 inhibitor. Preclinical studies have demonstrated ACY-1215 to have synergistic activity with taxanes. We have developed an algorithm (HDAC6 score) based on mRNA expression profiling to evaluate the HDAC6 activity of individual tumor samples. Methods: In this open-label phase Ib trial, patients (pts) received ACY-1215 PO daily for 21 days of each 28-day cycle with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 until progression of disease or unacceptable toxicity. Entry criteria included men or women with any MBC subtypes. Measurable diseae was not required. The primary objective was to establish the maximum tolerated dose (MTD) of ACY-1215 with nab-paclitaxel. Dose escalation employed a time-to-event continual reassessment method (TITE-CRM) and the MTD was defined as the dose combination associated with a target probability of dose limiting toxicity (DLT) of 0.25.The TITE-CRM used an empirical dose-toxicity model (n=16 evaluable pts), starting at 120 mg to a maximum dose of 240 mg daily (qd). HDAC score was performed retrospectively on primary and/or metastatic tissue.Results:Seventeen pts were accrued between March 2016-Feb 2018; 16 were evaluable. Of evaluable pts, the median age was 57.5 years (range: 41-78), 14 were female (87.5%), 3 had triple negative MBC, and 13 hormone receptor (HR)+/HER2- MBC. The mean number of prior lines was 4 (range: 0-9). The first pt started at 120 mg qd, the second at 180 mg qd, and the rest at 240 mg qd. No DLTs were seen in the DLT window, and thus the MTD was not reached. Grade III events related to nab-paclitaxel included neutropenia (n=1), peripheral neuropathy (n=1), and 1 grade IV neutropenia. Grade III syncope related to ACY-1215 was observed in 2 pts. In the 16 evaluable pts, the following were best responses: 1 partial response (PR), 11 stable disease (SD), and 4 progressive disease (PD: 2 TNBC, 2 HR+/HER2-). One patient with SD remains on treatment since Feb 2018 (17 months). Median progression free survival (PFS) was 5.3 months [95% confidence interval (CI): 4.45-11.0]. In evaluable pts with accessible tissue (n=9), pts with high HDAC6 score (n=6: cutoff \u003e -0.1) had a significantly improved PFS compared to low HDAC6 score (n=3, HR: 1.2-115, 6.6 months vs. 2.0 months, respectively p=0.01). Conclusions: ACY-1215 240 mg qd is safe and tolerable with weekly nab-paclitaxel. Clinical activity has been observed, with the majority of pts demonstrating SD and 1 with a PR. In this phase 1b trial, high HDAC6 score associates with longer PFS. HDAC6 score should be evaluated in larger trials as a predictor of response to HDAC6 inhibition. Citation Format: Kevin Kalinsky, Cody Chiuzan, Maika Onishi, Meghna S Trivedi, Melissa Accordino, Tizita Zeleke, Qingfei Pan, Sean Kelly, Erin Honan, Ruby Wu, Kathleen Fenn, Katherin D Crew, Dawn L Hershman, Matthew Maurer, Jiyang Yu, Jose Silva. Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-27.