title: A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors.
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.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
authors.forename: Nuttapong
authors.initials: N
authors.lastname: Ngamphaiboon
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Thanyanan
authors.initials: T
authors.lastname: Reungwetwattana
authors.forename: Dawn
authors.initials: D
authors.lastname: DePaolo
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: William
authors.initials: W
authors.lastname: Brady
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010671:Phenylurea Compounds; D011725:Pyridines; C118739:entinostat; D009536:Niacinamide; D000077157:Sorafenib