GPI-04-0001 was a Phase II, non-randomized, open label, single arm study that was conducted at approximately 30 sites, primarily in the United States, Europe and Russia. It assessed the efficacy, safety, and tolerability of romidepsin as a treatment for cutaneous T-cell lymphoma (CTCL). Study patients (pts) received romidepsin in a dose of 14 mg/m^2 intravenously over 4 hours on Days 1, 8 and 15 of each 28-day cycle. The duration of study treatment was 6 cycles although pts who showed an objective response or stable disease could continue to receive therapy, at the discretion of the investigator, until disease progression or another withdrawal criterion was met.

Responses were evaluated according to a composite assessment (Objective Primary Disease Response Evaluation Criteria [OPDREC]) that included cutaneous manifestations of disease, lymph node involvement, and circulating malignant T-cells (Sézary cells). Skin involvement was measured using a weighted body surface area skin assessment tool (WBSA/SWAT) or an erythroderma score, depending upon the pt's disease. Disease response was assessed by the Investigators and an Independent Response Review Committee (IRRC) with the IRRC assessment considered supportive of the Investigator's evaluations using the following criteria:

Complete Response (CR):

• Complete resolution of skin patches, skin plaques, and skin tumors, or erythroderma
• No evidence of abnormal lymph nodes
• Absence of circulating Sézary cells.
• No evidence of new tumors (cutaneous or non-cutaneous)
• Findings confirmed by skin biopsy

Clinical complete response (CCR):

- Same as CR but without skin biopsy

Partial Response (PR):

• ≥50% improvement in the summation of (change in Skin + change in Lymph Node + change in Peripheral Blood) with
• At least >30% improvement in Skin and
• No worsening in Lymph Node or Sézary cells.
• No evidence of new tumors (cutaneous/non-cutaneous)

Stable Disease (SD):

• Not enough improvement or worsening in the summation of (change in Skin + change in Lymph Node + change in Peripheral Blood to qualify as PR or PD
• No evidence of new tumors (cutaneous/non-cutaneous)

SD90:

- SD90 was defined as documented evidence of SD for at least 90 Days Duration

Progressive Disease (PD):

• Evidence of new tumor (cutaneous or non-cutaneous), OR
• >25% worsening in the summation of (change in Skin + change in Lymph Node + change in Peripheral Blood) with >15% worsening in change in Skin.

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.