Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma

Richard L Piekarz, Robin Frye, Maria Turner, John J Wright, Steven L Allen, Mark H Kirschbaum, Jasmine Zain, H Miles Prince, John P Leonard, Larisa J Geskin, Craig Reeder, David Joske, William D Figg, Erin R Gardner, Seth M Steinberg, Elaine S Jaffe, Maryalice Stetler-Stevenson, Stephen Lade, A Tito Fojo, Susan E Bates, Richard L Piekarz, Robin Frye, Maria Turner, John J Wright, Steven L Allen, Mark H Kirschbaum, Jasmine Zain, H Miles Prince, John P Leonard, Larisa J Geskin, Craig Reeder, David Joske, William D Figg, Erin R Gardner, Seth M Steinberg, Elaine S Jaffe, Maryalice Stetler-Stevenson, Stephen Lade, A Tito Fojo, Susan E Bates

Abstract

PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
(A) This patient with Sézary syndrome had progression of disease after denileukin diftitox and alemtuzumab. He remains in complete response after 63 months. (B) This patient with mycosis fungoides had progression of disease after psoralen with ultraviolet A therapy, etretinate, interferon alfa, and methotrexate. The patient demonstrated a good response that lasted 8 months.
Fig A1.
Fig A1.
Structure of romidepsin (FK228).
Fig A2.
Fig A2.
Schedule of administration.
Fig A3.
Fig A3.
Plot of area under the curve extrapolated to infinity (AUCinf) by dose level. Each circle represents the romidepsin exposure (AUCinf) for a single patient after the first treatment (42 patients receiving 14 mg/m2 and three patients receiving 18 mg/m2). The black line represents the mean for each dose level. Significant interindividual variability was observed, with AUCinf ranging from 333.15 to 3301.37 hr × ng/mL.
Fig A4.
Fig A4.
This patient experienced progression of disease after combination therapy with cyclophosphamide, vincritine, and prednisone and had a partial response on romidepsin that lasted 2 months.
Fig A5.
Fig A5.
Kaplan-Meier curves of progression-free survival of patients with best response of complete response (CR) or partial response (PR), patients with stable disease (SD), and patients with progressive disease (PD) or nonevaluable (NE) patients.

Source: PubMed

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