General Information

Istodax (romidepsin) is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors.

Istodax is specifically indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Istodax is supplied as solution for intravenous administration. The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

Clinical Results

FDA Approval
The FDA approval of Istodax was was based upon two prospective multicenter, single-arm clinical studies in 167 subjects. The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR).

Study One
This study enrolled 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. The subjects were treated with Istodax at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. The overall response rate (ORR) was 34% and the complete response rate was 6%. The median response duration was 15 months and the median time to first response was 2 months. The median time to CR was 6 months.

Study Two
This study enrolled 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. The subjects were treated with Istodax at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. The ORR was 35% and the CR rate was 6%. The median response duration was 11 months and the median time to first response was 2 months. The median time to CR was 4 months.

Mechanism of Action

Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

Literature References

Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, Geskin LJ, Reeder C, Joske D, Figg WD, Gardner ER, Steinberg SM, Jaffe ES, Stetler-Stevenson M, Lade S, Fojo AT, Bates SE Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009 Nov 10;27(32):5410-7

Woo S, Gardner ER, Chen X, Ockers SB, Baum CE, Sissung TM, Price DK, Frye R, Piekarz RL, Bates SE, Figg WD Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2009 Feb 15;15(4):1496-503