A Single Agent Phase II Study of Romidepsin (Depsipeptide, FK228) in the Treatment of Cutaneous T-cell Lymphoma (CTCL)
Condition: Cutaneous T-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous
Intervention: romidepsin (depsipeptide, FK228)
Intervention description: Study patients received romidepsin at 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 patients 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.
Intervention MeSH terms: Romidepsin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 102.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: romidepsin

Summary:

      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.
    

Eligibility criteria:

        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.