slow accrual

This pilot clinical trial studies romidepsin in treating patients with graft-versus-host disease (GVHD) that has not responded to treatment with steroids. Romidepsin may be an effective treatment for graft-versus-host disease caused by a bone marrow or stem cell transplant.

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

Participants > 18 years old with steroid (or IST) refractory aGVHD or cGVHD were enrolled.

Adverse event data was collected over 60 days.

CTCAE version 4.0 was utilized.