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.