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

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.

Conflict of interest statement

MG: employment, Arizona Center for Cancer Care; stock, Medelis, Care Mission USA; honoraria, Deciphera; consulting/advisory role, Deciphera, RedHill Biopharma, Salarius; research funding, AbbVie, Acetylon, Celgene, a Bristol-Myers Squibb Company, Celldex, Corcept, Calithera, Deciphera, Eisai, Endocyte, Eli Lilly, Five Prime, Genentech, Plexxikon, Pfizer, MedImmune, Merck, OncoMed. GS: research funding, Eli Lilly, Merck KGaA/EMD Serono, Merck, Sierra Oncology; consulting/advisory role, Almac, Angiex, Astex, Bayer, Bicycle Therapeutics, Cybrexa Therapeutics, Daiichi Sankyo, Eli Lilly, Fusion Pharmaceuticals, G1 Therapeutics, Ipsen, Merck KGaA/EMD Serono, Pfizer, Roche, Sierra Oncology. DJ: consulting/advisory role, Eisai, EMD Serono, Novartis. BL, YLB, and CD: employment, Bristol Myers Squibb; stock, Bristol Myers Squibb. AZ: employment, Celgene, a Bristol-Myers Squibb Company; stock, Bristol Myers Squibb. JC: employment, Bristol Myers Squibb; stock, Bristol Myers Squibb; research funding, Celgene, a Bristol-Myers Squibb Company; travel, Celgene, a Bristol-Myers Squibb Company. RH: consulting/advisory, Amgen, GlaxoSmithKline; research funding, Abbisko, AbbVie, Actuate, Alkermes, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Biomedical, Calithera, Celgene, a Bristol-Myers Squibb Company, FujiFilm, Genmab, GlaxoSmithKline, Infinity, InhibRx, Merck, Mersana, Meryx, Nektar, Pfizer, Puma, RAPT Therapeutics, Regeneron, Rgenix, Sanofi, Seattle Genetics, Sutro, Takeda, Xencor. The authors declare that this study received funding from Celgene Research S.L.U. The funder was involved in the study design, collection, analysis, interpretation of data, and funded the writing of this article. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Gordon, Shapiro, Sarantopoulos, Juric, Lu, Zarotiadou, Connarn, Le Bruchec, Dumitru and Harvey.

Figures

Figure 1

Study design of the phase Ib trial of citarinostat plus paclitaxel in patients with advanced solid tumors. a28-day cycles with citarinostat administered orally once daily on days 1 to 21 at all doses and paclitaxel administered intravenously on days 1, 8, and 15. bAn additional 360-mg cohort was allowed if the maximum tolerated dose was not reached.

Figure 2

(A) Tumor shrinkage by enrolled population (1 patient with ovarian cancer did not have a postbaseline efficacy assessment and was not included in this analysis) and (B) treatment duration by individual patients (safety population). aReceived citarinostat as monotherapy beginning in cycle 25. bReceived citarinostat as monotherapy beginning in cycle 11 (paclitaxel withdrawn due to grade 3 neuropathy). GE, gastroesophageal.

Figure 3

Histone (A) and tubulin (B) acetylation time course (average and SEM for patients treated at indicated levels on cycle 1 day 1). Dose levels indicated are 180, 360, and 480 mg of citarinostat orally once daily. Note: measurements are made on n = 3 at 180-mg level, n = 11 at 360-mg level, and n = 6 at 480-mg level. Cycle 1 day 15 measurements have similar profiles (data not shown). ACY, ACY-241 (citarinostat); MFI, mean fluorescence intensity; PTX, paclitaxel.