Romidepsin in Treating Patients With Steroid-Refractory Graft-versus-Host Disease

PRIMARY OBJECTIVES:

I. To determine if romidepsin should be developed as a therapy for patients with
steroid-refractory GVHD.

OUTLINE:

Patients receive romidepsin intravenously (IV) over 4 hours on days 1, 8, and 15. Treatment
repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months.

Inclusion Criteria:

- Patients with steroid (or immunosuppressive therapy [IST]) refractory acute GVHD
(aGVHD) or chronic GVHD (cGVHD)

- Absolute neutrophil count >= 750/mm^3

- Platelet count >= 50,000/mm^3

- Corrected QT interval (QTc) =< 480 msec

- Bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
ULN

- Serum potassium >= 3.8 mmol/L

- Serum magnesium >= 1.8 mg/dL

- Serum creatinine =< 2.0 mg/dl

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3

- Patients may undergo electrolyte repletion therapy to meet eligibility requirements

- Patients must be scheduled for tapering doses of (or no longer treated with):

- Cyclosporine;

- Tacrolimus;

- Sirolimus;

- Steroids (patients may be on physiologic doses of steroids)

- Patients receiving extracorporeal photopheresis must discontinue extracorporeal
photopheresis or placed on a tapering schedule;

- Any prior therapy for GVHD must be completed and discontinued with the exception of
the above;

- Patients with breakpoint cluster region (bcr)-ABL proto-oncogene 1 (abl) associated
malignancies may be on a tyrosine kinase inhibitor as malignant disease therapy or
prophylaxis

- There must be no uncontrolled active infections or medical conditions that the
investigator feels will compromise the safety of the treatment and/or the assessment
of the efficacy of therapy

- The patient must be aware of the high risk and experimental nature of the treatment
and provide informed consent

- Negative serum pregnancy test at the time of enrollment for females of childbearing
potential

- For males and females of child-producing potential, use of effective contraceptive
methods during the study and for at least 6 months after the last dose of romidepsin

Exclusion Criteria:

- Active/uncontrolled infection

- Evidence of relapsed disease

- Life expectancy < 12 weeks

- Pregnant or breast feeding females

- Prior therapy with romidepsin

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are
seropositive because of hepatitis B virus vaccine are eligible

- Any known cardiac abnormalities such as:

- Congenital long QT syndrome

- QTc interval >= 480 milliseconds;

- Myocardial infarction within 6 months of course 1, day 1 (C1D1); subjects with a
history of myocardial infarction 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 have a stress imaging
study and, if abnormal, angiography to define whether or not CAD is present;

- An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
of >= 2 mm, measured from isoelectric line to the ST segment); 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 multi gated
acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance
imaging (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 cardiomegaly or restrictive cardiomyopathy from prior treatment or
other cause;

- Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)

- 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; or

- Patients taking drugs leading to significant QT prolongation must have an ECG prior
to each treatment

- Concomitant use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
inhibitors

- Concomitant use of medications known to induce a disulfiram-like reaction to alcohol