Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Michael S Gordon; Geoffrey I Shapiro; John Sarantopoulos; Dejan Juric; Brian Lu; Angeliki Zarotiadou; Jamie N Connarn; Yvan Le Bruchec; Calin Dan Dumitru; R Donald Harvey

doi:10.3389/fonc.2021.786120

Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Front Oncol. 2022 Jan 7:11:786120. doi: 10.3389/fonc.2021.786120. eCollection 2021.

Authors

Affiliations

¹ Departments of Hematology and Medical Oncology, HonorHealth Research Institute, Scottsdale, AZ, United States.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
³ Department of Medicine, Division of Medical Oncology & Hematology, Institute for Drug Development, Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX, United States.
⁴ Massachusetts General Hospital Cancer Center, Boston, MA, United States.
⁵ Department of Medicine, Harvard Medical School, Boston, MA, United States.
⁶ Bristol Myers Squibb, Princeton, NJ, United States.
⁷ Celgene Research S.L.U., a Bristol-Myers Squibb Company, Boudry, Switzerland.
⁸ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and Emory University School of Medicine, Atlanta, GA, United States.

Abstract

Background: 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.

Methods: Patients 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.

Results: Twenty 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.

Conclusions: The 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).

Keywords: HDAC inhibition; advanced solid tumors; citarinostat; combination therapy; epigenetics; histone acetylation; histone deacetylase; paclitaxel.

Associated data

ClinicalTrials.gov/NCT02551185