title: Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.
abstract: OBJECTIVE
  Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile.
  
  
  METHODS
  Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m(2) on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1-3 and 8-10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2.
  
  
  RESULTS
  All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST.
  
  
  CONCLUSIONS
  Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA, ursula_matulonis@dfci.harvard.edu.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Berlin
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.forename: Christin
authors.initials: C
authors.lastname: Whalen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Obermayer
authors.forename: Richard
authors.initials: R
authors.lastname: Penson
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.forename: Susana
authors.initials: S
authors.lastname: Campos
authors.forename: Carolyn
authors.initials: C
authors.lastname: Krasner
authors.forename: Neil
authors.initials: N
authors.lastname: Horowitz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D000077337:Vorinostat; D000093542:Gemcitabine
chemical_list: D006877:Hydroxamic Acids; D003841:Deoxycytidine; D000077337:Vorinostat; D016190:Carboplatin; D000093542:Gemcitabine