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

This is a Phase II, non-randomized, open-label, single-arm trial. This study is designed on
the basis of complete response [CR or CR(u)] as the measure of efficacy, based on the best
overall response of each patient. The sample size of 65 patients evaluable for efficacy would
yield lower 95% confidence limits on the rate of CR + CR(u) that would range from 2.2% to
7.7%, if the observed rate of CR + CR(u) ranges from 8% to 15%. The study was amended to
include an Extension Phase, during which patients at non-US sites who are benefitting from
treatment can continue to receive romidepsin. The Extension Study Phase is active in EU
countries where currently no Marketing Authorisation exists for romidepsin. Patients may
remain on study until progressive disease occurs or they withdraw their consent and only
serious adverse events and study drug administration data will continue to be collected and
reported for these patients.

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).