title: A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study.
abstract: OBJECTIVE
  This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.
  
  
  METHODS
  Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.
  
  
  RESULTS
  Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8(+) T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3(+) CD8(+) T cells were larger in responders than nonresponders (P = 0.049).
  
  
  CONCLUSIONS
  This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3(+) CD8(+) T cells warrant further study.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Hematology and Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Scepura
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Ariel
authors.initials: A
authors.lastname: Lopez-Chavez
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Ari
authors.initials: A
authors.lastname: Frosch
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Thoracic Surgery Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland. gg496@georgetown.edu.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage; D013953:Thymus Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D057170:Translational Research, Biomedical / Q000379:methods; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D013449:Sulfonamides; D004317:Doxorubicin; D003520:Cyclophosphamide; C487081:belinostat; D002945:Cisplatin