A Trial of Romidepsin for Progressive or Relapsed Peripheral T-cell Lymphoma

Inclusion Criteria:

Patients must fulfill all of the following criteria to be eligible for study participation and have:

* Histologically confirmed PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy- type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous γδ T-cell lymphoma (excludes mycosis fungoides or Sezary syndrome), transformed mycosis fungoides, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL; anaplastic lymphoma kinase \[ALK\]-1 negative), or patients with ALK 1 expressing ALCL (ALK-1 positive) who have relapsed disease after autologous stem cell transplant (ASCT);
* Age ≥18 years;
* Written informed consent;
* Progressive disease following at least one systemic therapy or refractory to at least one prior systemic therapy;
* Measurable disease according to the International Workshop Response (IWC) criteria and/or measurable cutaneous disease;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
* Serum potassium ≥3.8 mmol/L and magnesium ≥0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria);
* Negative urine or serum pregnancy test on females of childbearing potential; and
* All women of childbearing potential must use an effective barrier method of contraception (either an intrauterine contraceptive device \[IUCD\] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male patients should use a barrier method of contraception 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) should be avoided due to a potential drug interaction.

Exclusion Criteria:

Patients are ineligible for entry if any of the following criteria are met:

* Known central nervous system (CNS) lymphoma \[computed tomography (CT) or magnetic resonance imaging (MRI) scans are required only if brain metastasis is suspected clinically\];
* Chemotherapy or immunotherapy within 4 weeks of study entry (6 weeks if nitrosoureas given);
* Initiation of corticosteroids during study (defined as 7 days prior to Cycle 1 Day 1\[C1D1\] until study drug discontinuation)

  * Patients treated with a pulse of steroids were to discontinue steroid use 7 days prior to C1D1 and have a repeat CT scan and disease assessment after discontinuation of corticosteroids and before starting romidepsin;
* Concomitant use of any other anti-cancer therapy;
* Concomitant use of any investigational agent;
* Use of any investigational agent within 4 weeks of study entry;
* Any known cardiac abnormalities such as:

  * Congenital long QT syndrome;
  * QTc interval \>480 milliseconds (msec);
  * A myocardial infarction within 6 months of C1D1. Patients with a history of myocardial infraction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;
  * Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
  * Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV. In any patient in whom there is doubt, the patient should be referred to a cardiologist for evaluation;
  * An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
  * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction \<40% by MUGA scan or \<50% by echocardiogram and/or MRI;
  * A known 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);
  * Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
  * Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria;
  * Any cardiac arrhythmia requiring anti-arrhythmic medication;
* Serum potassium \<3.8 mmol/L or serum magnesium \<0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria);
* Concomitant use of drugs that may cause a significant prolongation of the QTc;
* Concomitant use of CYP3A4 significant or moderate inhibitors;
* Concomitant use of therapeutic warfarin or another anticoagulant due to a potential drug interaction. Use of a small dose of a anticoagulant to maintain patency of venous access port and cannulas is permitted;
* Clinically significant active infection;
* Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;
* Previous extensive radiotherapy involving ≥30% of bone marrow (e.g., whole pelvis, half spine), excluding patients who have had total body irradiation as part of a conditioning regimen for ASCT;
* Major surgery within 2 weeks of study entry;
* Previous allogeneic stem cell transplant;
* Inadequate bone marrow or other organ function as evidenced by:

  * Hemoglobin \<9 g/dL (transfusions and/or erythropoietin are permitted);
  * Absolute neutrophil count (ANC) ≤1.0 × 10\^9 cells/L \[patients with neutropenia (ANC 1-1.5 10\^9 cells/L) as a function of their disease may be supported with granulocyte-colony stimulating factor (G-CSF)\];
  * Platelet count \<100 × 10\^9 cells/L or platelet count \<75 × 10\^9 cells/L if bone marrow disease involvement is documented;
  * Total bilirubin \>2.0 × upper limit of normal (ULN) or \>3.0 × ULN in the presence of demonstrable liver metastases;
  * Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) \>2.0 × ULN or \>3.0 × ULN in the presence of demonstrable liver metastases; or
  * Serum creatinine \>2.0 × ULN;
* Patients who are pregnant or breast-feeding;
* Coexistent second malignancy or history of prior solid organ malignancy within previous 3 years (excluding basal or squamous cell carcinoma of the skin, and in situ carcinoma of the cervix (CIN 1) that has been treated curatively);
* Any prior history of a hematologic malignancy (other than T-cell lymphoma);
* Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures; or
* Prior exposure to romidepsin (other histone deacetylase inhibitors are allowed).