Phase I trial of a new schedule of romidepsin in patients with advanced cancers.

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.
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.
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.
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.
AuthorsLaleh Amiri-Kordestani, Victoria Luchenko, Cody J Peer, Kambiz Ghafourian, James Reynolds, Deb Draper, Robin Frye, Sue Woo, David Venzon, John Wright, Monica Skarulis, William D Figg, Tito Fojo, Susan E Bates, Richard L Piekarz
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 16 Pg. 4499-507 (Aug 15 2013) ISSN: 1078-0432 [Print] United States
PMID23757352 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Copyright©2013 AACR.
Chemical References
  • Antibiotics, Antineoplastic
  • Depsipeptides
  • romidepsin
  • Adult
  • Aged
  • Antibiotics, Antineoplastic (pharmacology, therapeutic use)
  • Depsipeptides (pharmacology, therapeutic use)
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms (diagnosis, drug therapy, pathology)
  • Treatment Outcome

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