Abstract
BackgroundCitarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors.MethodsPatients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.ResultsTwenty patients were enrolled and received study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.ConclusionsThe combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m2 every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185).
Highlights
Histone deacetylases (HDACs) are commonly overexpressed in many types of cancers [1, 2], an observation that has led to the emergence of cancer therapies targeting HDACs [3]
The citarinostat dose was escalated (180, 360, or 480 mg) in combination with paclitaxel 80 mg/m2. Six of these patients (30%) received citarinostat 360 mg as part of an additional cohort to further evaluate the tolerability of the combination of citarinostat and paclitaxel and to confirm the RP2D in those with disease that had progressed following taxane therapy
Treatment discontinuations were due to progressive disease (PD; 80%), AEs (10%), physician decision (5%), and patient withdrawal (5%)
Summary
Histone deacetylases (HDACs) are commonly overexpressed in many types of cancers [1, 2], an observation that has led to the emergence of cancer therapies targeting HDACs [3]. Citarinostat (CC-96241; previously ACY-241) is an oral selective HDAC6 inhibitor that exhibits potent biochemical inhibition of HDAC6 with 13- to 18-fold reduced potency against the nuclear class I HDACs, including HDAC1, HDAC2, and HDAC3 [11]. In a preclinical study using A2780 ovarian cancer cells, treatment with citarinostat (300 nM) for 24 hours increased a-tubulin acetylation, which is consistent with tubulin deacetylase HDAC6 inhibition. Acetylation of histones (targeted by class I HDACs) was increased but only at citarinostat doses exceeding 1 mM. Citarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors
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