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A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors

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Abstract

Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional “3 + 3” dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks. Sorafenib was administered as a continuous oral dose, escalating from 200 to 400 mg twice daily. A treatment cycle was 28 days. A total of 31 patients with advanced solid tumors were enrolled on the study. The three dose-limiting toxicities (DLTs) observed were grade 3 hand-foot syndrome, nausea/vomiting, and fatigue. MTD was not reached. The recommended phase II dose was defined as the full dose of the respective drugs administered individually. The most common grade 3–4 toxicities were muscle weakness (13 %), skin rash (10 %), fatigue (6 %), diarrhea (6 %), and hand-foot syndrome (3 %). One NSCLC patient achieved a partial response. Two patients (adenocarcinoma of GE junction and Hurthle cell carcinoma of the thyroid) were on the study for more than 9 months with stable disease. The combination of entinostat and sorafenib was well tolerated. Entinostat 10 mg orally once every 2 weeks in combination with sorafenib 400 mg orally twice daily, representing full single agent doses of each drug was identified as the recommended phase 2 dose (RP2D). These data support future clinical development of the combination of entinostat and sorafenib.

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The authors declare that they have no conflict of interest.

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  1. Nuttapong Ngamphaiboon & Thanyanan Reungwetwattana

    Present address: Department of Internal Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand

Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Nuttapong Ngamphaiboon, Grace K. Dy, Wen Wee Ma, Yujie Zhao, Thanyanan Reungwetwattana, Dawn DePaolo, Yi Ding, William Brady, Gerald Fetterly & Alex A. Adjei

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  1. Nuttapong Ngamphaiboon
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  2. Grace K. Dy
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Correspondence to Alex A. Adjei.

Additional information

Supported by a Drug Development Research Professorship from Conquer Cancer Foundation (AAA) and by grant P30 CA016056 from NCI

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Ngamphaiboon, N., Dy, G.K., Ma, W.W. et al. A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs 33, 225–232 (2015). https://doi.org/10.1007/s10637-014-0174-6

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  • DOI: https://doi.org/10.1007/s10637-014-0174-6

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