A Single Agent Phase II Study of Romidepsin (Depsipeptide, FK228) in the Treatment of Cutaneous T-cell Lymphoma (CTCL)

Inclusion Criteria: Patients had to fulfill all of the following criteria to be eligible for study participation:

• Males or non-pregnant females aged 18 or over.
• Histologically confirmed diagnosis of CTCL, including mycosis fungoides and Sézary syndrome.
• Patients with CTCL stages II-A, II-B, III, and IV-A only.
• Patients with CTCL stage IB who had relapsed following previous therapy and where, in the investigator's opinion, the potential benefit of treatment with romidepsin outweighed the possible risks.
• Patients who had failed standardized skin-directed therapy and had had at least one course of systemic therapy, such as interferon, Ontak®, chemotherapy or Targretin®, etc., which they were deemed to have failed.
• Anticipated life expectancy greater than six months.
• Written informed consent to participate in the study.

Exclusion Criteria: Patients were ineligible for entry if any of the following criteria were met:

• ECOG Performance Status >1.
• Patients who had not received at least 1 course of prior systemic therapy for CTCL.
• Visceral involvement i.e. Stage 4B disease (lymphadenopathy was allowed).
• Patients with known cardiac abnormalities such as:
• Congenital long QT syndrome
• QTc (Corrected QT interval on ECG) interval >480 milliseconds
• Any cardiac arrhythmia requiring anti-arrhythmic medication.
• Patients who had had a myocardial infarction within 12 months of study entry.
• Patients who had a history of coronary artery disease (CAD) e.g. angina Canadian class II to IV. In any patient in whom there was doubt, the patient should have had a stress imaging study and exercise electrocardiogram (ECG) and, if abnormal, angiography to define whether or not CAD was present.
• Patients with an ECG recorded at screening showing evidence of cardiac ischaemia (ST depression of >=2 mm). If in any doubt, the patient should have had a stress imaging study and exercise ECG and, if abnormal, angiography to define whether or not CAD is present.
• Patients with congestive heart failure that met New York Heart Association class II to IV definitions and/or ejection fraction <40% by multiple gated acquisition (MUGA) scan or <50% by echocardiogram and/or magnetic resonance imaging (MRI)
• Patients with a history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest, unless currently addressed with an automatic implantable cardioverter defibrillator (AICD).
• Patients with hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above).
• Patients with uncontrolled hypertension, i.e. >=160/95 mmHg.
• Concomitant use of any anti-cancer therapy.
• Concomitant use of warfarin (due to a drug interaction).
• Concomitant use of any investigational agent.
• Use of any investigational agent within 4 weeks of study entry.
• Concomitant use of drugs which may cause a prolongation of the QTc interval.
• Patients with a potassium level of <3.5 mmol/L and a magnesium level of <0.8 mmol/L.
• Clinically significant active infection.
• Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
• Inadequate bone marrow or other organ function, as evidenced by:
• unsupported haemoglobin <9.0 g/dL (transfusions and/or erythropoietin were permitted);
• absolute neutrophil count (ANC) <=1.5 x 10^9/L;
• platelet count <100 x 10^9/L;
• total bilirubin >1.25 x upper limit of normal (ULN) for institution,
• aspartate transaminase/glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/ glutamic pyruvic transaminase (ALT/SGPT) >2.0 x ULN, serum creatinine >2.0 x ULN for age and sex;
• Coexistent second malignancy or history of prior malignancy within previous 5 years (excluding basal or squamous cell carcinoma of the skin or cervical epithelial neoplasm [CIN1, carcinoma in situ] that had been treated curatively).
• Any significant medical or psychiatric condition that might have prevented the patient from complying with all study procedures.
• Patients who were pregnant or breast-feeding. All women of child bearing potential were to use an effective method of contraception (either an intrauterine device or a double barrier method using condoms or a diaphragm plus spermicide) during the study and for at least one month after receiving the last dose of romidepsin. Male patients were to use a barrier method of contraception (condoms) during the treatment period and for at least 1 month thereafter. Hormonal methods of contraception such as the contraceptive pill or patch (particularly those containing ethinyl estradiol) were to be avoided due to a potential drug interaction.
• Use of topical steroids in the previous 2 weeks or systemic steroids in the previous 4 weeks.
• Having previously given consent to participate in this study.
• Concomitant use of CYP3A4 inhibitors.