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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Pilot Study of Romidepsin for Therapy of Graft-versus-Host Disease

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: romidepsin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (romidepsin)<br>Patients receive romidepsin 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. | Drug: romidepsin<br>* Given IV<br>* Other names: Istodax;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of aGVHD |  | At 28 days after initiation of romidepsin | 
| Incidence of cGVHD |  | At 1 month after initiation of romidepsin | 
| Incidence of cGVHD |  | At 3 months after initiation of romidepsin | 
| Incidence of cGVHD |  | At 6 months after initiation of romidepsin | 
| Incidence of cGVHD |  | At 9 months after initiation of romidepsin | 
| Incidence of cGVHD |  | At 12 months after initiation of romidepsin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Duration of Immunosuppressive Therapy |  | Up to 12 months after initiation of romidepsin | 
| Rate of Documented Infection |  | Up to 12 months after initiation of romidepsin | 
| T Cell Kinetics - Reconstitution |  | Up to 12 months after initiation of romidepsin |