title: Phase I trial of a new schedule of romidepsin in patients with advanced cancers.
abstract: OBJECTIVE
  Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.
  
  
  METHODS
  Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes.
  
  
  RESULTS
  Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases.
  
  
  CONCLUSIONS
  A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Laleh
authors.initials: L
authors.lastname: Amiri-Kordestani
authors.forename: Victoria
authors.initials: V
authors.lastname: Luchenko
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.forename: Kambiz
authors.initials: K
authors.lastname: Ghafourian
authors.forename: James
authors.initials: J
authors.lastname: Reynolds
authors.forename: Deb
authors.initials: D
authors.lastname: Draper
authors.forename: Robin
authors.initials: R
authors.lastname: Frye
authors.forename: Sue
authors.initials: S
authors.lastname: Woo
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Monica
authors.initials: M
authors.lastname: Skarulis
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C087123:romidepsin