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Updated: Oct 19, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Selective Histone Deacetylase Inhibitor ACY-241 (Citarinostat) Plus Nivolumab in Advanced Non-Small Cell Lung Cancer:
Mark M Awad1, Yvan Le Bruchec2, Brian Lu2
1Lowe Center for Thoracic Oncology and Dana-Farber Cancer Institute, Boston, MA, United States.
Background:
Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer (NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
Methods:
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
Results:
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3+ T cells was observed following treatment.
Conclusions:
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
Clinical Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
Insights
This study found that the maximum tolerated dose of ACY-241 plus nivolumab in advanced non-small cell lung cancer patients was 360 mg. The combination showed feasibility and antitumor activity, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Histone deacetylase (HDAC) overexpression is linked to poor outcomes in various cancers.
- Selective HDAC6 inhibition shows preclinical promise, particularly in combination with immune checkpoint inhibitors due to immunomodulatory effects.
- Previous studies suggest potential for HDAC inhibitors combined with chemotherapy or EGFR inhibitors in non-small cell lung cancer (NSCLC), but toxicity is a concern.
Purpose of the Study:
- To investigate the safety and tolerability of combining ACY-241 (a selective HDAC6 inhibitor) with nivolumab in advanced NSCLC patients.
- To determine the maximum tolerated dose (MTD) of the ACY-241 and nivolumab combination.
- To explore preliminary antitumor activity and pharmacodynamic effects of the combination therapy.
Main Methods:
- A phase Ib, multicenter, single-arm, open-label, dose-escalation study.
- Patients received oral ACY-241 (180, 360, or 480 mg daily) plus intravenous nivolumab (240 mg every 2 weeks).
- Primary endpoint was MTD; secondary endpoints included safety, tolerability, and antitumor response.
Main Results:
- The MTD of ACY-241 was determined to be 360 mg daily.
- Common grade ≥ 3 adverse events included dyspnea and pneumonia (18% each).
- Observed responses included complete and partial responses (PRs) at lower ACY-241 doses, with 3 PRs at the 360 mg dose. Treatment increased histone/tubulin acetylation and CD3+ T cell infiltration.
Conclusions:
- The combination of ACY-241 and nivolumab is feasible in previously treated advanced NSCLC patients.
- The identified MTD of 360 mg ACY-241 provides a basis for further clinical investigation.
- Preliminary data suggest potential antitumor activity for this combination therapy.
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