Abstract OT1-01-10: Multi-center phase IB trial of ACY-1215 (Ricolinostat) combined with nab-paclitaxel in unresectable or metastatic breast cancer
Authors: Onishi M , Chiuzan C , Fasano J , Crew K , Accordino M , Tiersten A , Shapiro C , Jarpe M , Qualye S , Trede N , Wheeler C , Hershman D , Silva J , Maurer M , Kalinksy K 
Published: March 2017

Abstract
BACKGROUND:
HDAC6, a cytoplasmic histone deacetylase, targets non-chromatin substrates including tubulin, HSP90, and cortactin, playing an important role in cell-cell interactions, motility, chaperone function, and protein degradation. ACY-1215 (Ricolinostat) is an orally active, selective HDAC6 inhibitor. Preclinical studies have demonstrated ACY-1215 to have activity in breast cancer, synergistic cytotoxicity with taxanes, possibly due to combined effects on microtubule stabilization, and protective effects against neurodegeneration and potentially peripheral neuropathy. Analysis of human primary breast cancer gene expression data has identified a set of 162 genes corresponding to a HDAC6 master regulator (MR) score that correlates with IC50 or sensitivity to ACY-1215, and may serve as a potential biomarker.
TRIAL DESIGN:
This is an open-label, multicenter Phase 1b trial (NCT01323751) of ACY-1215 combined with nab-paclitaxel in unresectable or metastatic breast cancer. Patients will receive ACY-1215 daily for 21 days of each 28-day cycle in combination with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 until progression of disease or unacceptable toxicity.
KEY ELIGIBILITY CRITERIA:
Patients aged ≥ 18 years with unresectable or metastatic breast adenocarcinoma, measurable or non-measurable disease, an ECOG performance status of 0 to 1, baseline toxicities and symptoms grade ≤1, and at least 2 weeks since prior treatment.
STATISTICAL METHODS:
Dose escalations will be performed according to the time to event continual reassessment method (TITE-CRM), starting at 120 mg to a maximum dose of 240 mg. The maximum tolerated dose (MTD) will be identified as the dose level associated with a target probability of dose limiting toxicity (DLT) of 0.25. The TITE-CRM will use an empirical dose-toxicity model, with a sample size of 24. The dose-toxicity model is calibrated to select a dose that yields between 17 and 33% DLT, which will be the recommended phase II dose (RP2D).
OBJECTIVES:
The primary objective of this trial is to determine the MTD of ACY-1215 in combination with weekly nab-paclitaxel. Secondary objectives include the evaluation of safety and tolerability, progression free survival, overall response rate (measured by RECIST 1.1), and clinical benefit rate. Exploratory analyses will assess pharmacokinetics and pharmacodynamics, correlation of biomarkers including the HDAC6 score with response, and the effect of ACY-1215 on taxane-induced peripheral neuropathy.
ACCRUAL: Target Accrual is 24 patients.
CONTACT INFORMATION:
Kevin Kalinsky, MD, MS 212-305-1945 kk2693@cumc.columbia.edu.
Citation Format: Onishi M, Chiuzan C, Fasano J, Crew K, Accordino M, Tiersten A, Shapiro C, Jarpe M, Qualye S, Trede N, Wheeler C, Hershman D, Silva J, Maurer M, Kalinksy K. Multi-center phase IB trial of ACY-1215 (Ricolinostat) combined with nab-paclitaxel in unresectable or metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-10.