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

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.